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Synthesis of ZnO nanoparticles by two different methods & comparison of their structural, antibacterial, photocatalytic and optical properties

Md Jahidul Haque 1 , Md Masum Bellah 1 , Md Rakibu Hassan 1 and Suhanur Rahman 1

Published 16 March 2020 • © 2020 The Author(s). Published by IOP Publishing Ltd Nano Express , Volume 1 , Number 1 Citation Md Jahidul Haque et al 2020 Nano Ex. 1 010007 DOI 10.1088/2632-959X/ab7a43

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1 Department of Glass & Ceramic Engineering, Rajshahi University of Engineering & Technology (RUET), Rajshahi-6204, Bangladesh

Md Jahidul Haque https://orcid.org/0000-0001-7945-5937

• Received 23 December 2019
• Revised 3 February 2020
• Accepted 26 February 2020
• Published 16 March 2020

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Method : Single-anonymous Revisions: 1 Screened for originality? Yes

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In this work, two different methods (sol-gel and biosynthesis) were adopted for the synthesis of zinc oxide (ZnO) nanoparticles. The leaf extract of Azadirachta Indica (Neem) was utilized in the biosynthesis scheme. Structural, antibacterial, photocatalytic and optical performances of the two variants were analyzed. Both variants demonstrated a wurtzite hexagonal structure. The biosynthesized variant (25.97 nm) exhibited smaller particles than that of the sol-gel variant (33.20 nm). The morphological analysis revealed that most of the particles of the sol-gel variant remained within the range of 15 nm to 68 nm while for the biosynthesized variant the range was 10–70 nm. The antibacterial assessment was redacted by using the agar well diffusion method in which the bacteria medium was Escherichia coli O157: H7. The zone of inhibition of bacterial growth was higher in the biosynthesized variant (14.5 mm). The photocatalytic performances of the nanoparticles were determined through the degradation of methylene blue dye in which the biosynthesized variant provided better performance. The electron spin resonance (EPR) analysis revealed that the free OH · radicals were the primary active species for this degradation phenomenon. The absorption band of the sol-gel and biosynthesized variants were 363 nm and 356 nm respectively. The optical band gap energy of the biosynthesized variant (3.25 eV) was slightly higher than that of the sol-gel variant (3.23 eV). Nevertheless, the improved antibacterial and photocatalytic responses of the biosynthesized variants were obtained due to the higher rate of stabilization mechanism of the nanoparticles by the organic chemicals (terpenoids) present in the Neem leaf extract.

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1. Introduction

As a rapidly growing sector in materials science, nanotechnology and nanoscience deal with materials that have particles within a size range of 1 to 100 nm and a high surface-to-volume ratio [ 1 ]. In general form, these particles are termed as nanoparticles (NPs) which exhibit highly controllable physical, chemical and biological properties in the atomic and sub-atomic levels. However, these unique features create opportunities to use them in different sectors such as electronics, optoelectronics, agriculture, communications, and biomedicine [ 2 , 3 ].

Although, several NPs are showing their effectiveness in different sectors of technology, but zinc oxide (ZnO) NPs have gained much more importance in the recent years due to their attractive and outstanding properties such as high chemical stability, high photostability, high electrochemical coupling coefficient and a wide range of radiation absorption [ 4 ]. Again, ZnO NPs are also recognized as n-type multi-functional semiconductor materials that have a wide band gap of 3.37 eV and exciton binding energy up to 60 meV even at room temperature [ 1 ]. Nowadays, ZnO NPs are predominantly used as antimicrobial agents, delivering systems vaccines and anti-cancer systems, photocatalyst, biosensors, energy generators and bio-imaging materials [ 5 – 7 ]. Among themselves, the photocatalytic application of ZnO NPs is significant. However, the photocatalytic performance of ZnO NPs can be significantly enhanced by adopting two ways. The first one involves the reduction of particle sizes by using efficient synthesis methods, while the second one involves the change of structural morphology by the incorporation of several elements (such as metal, non-metal, noble metal, transition metal, etc) into the crystal structure of ZnO NPs. However, in this work, we will proceed by adopting the first one.

Several fabrication techniques are used to produce ZnO NPs such as thermal hydrolysis techniques, hydrothermal processing, sol-gel method, vapor condensation method, spray pyrolysis and thermochemical techniques [ 8 ]. Nevertheless, recently a new synthesis method has been introduced and that is called biosynthesis scheme in which the NPs are prepared by using biological materials having significant reducing and stabilizing features. Moreover, NPs with variable size and shape can be achieved through this process.

Researchers proposed several possible plant extracts and fungal biomasses that were used in the green synthesis of ZnO NPs such as Aloe Barbadensis Miller (Aloe Vera) leaf extract [ 9 ], Poncirus trifoliate leaf extract [ 10 ], Parthenium hysterophorus L. (Carrot grass) leaf extract [ 11 ], Aspergillus aeneus [ 12 ], Calotropis procera latex [ 13 ], Sedum alfredii Hance [ 14 ], Physalis alkekengi L. [ 15 ], etc. However, the smaller particle size of ZnO NPs was observed by using Poncirus trifoliate leaf extract (8.48–32.51 nm), while for others, the results were satisfactory. In addition, another potential element for the preparation of ZnO NPs through the biosynthesis method is considered to be a leaf extract of Azadirachta indica (Neem leaf). The leaf extract contains highly active phytochemicals and enzymes that participate in the oxidation or reduction reactions that occur during the fabrication method and manipulate the bulk ZnO to convert into ZnO NPs [ 16 ]. Moreover, Neem leaf provides significant biological restrictions against bacterial growth and fungal growth [ 17 ].

The present study focused on the preparation of ZnO NPs by two different methods. The first one is the sol-gel method, while the second one is the biosynthesis method in which the Neem leaf extract was used as a mandatory element. A comparison of the properties (structural, antibacterial, photocatalytic and optical) between the two variants of ZnO NPs was performed. Here, the sol-gel synthesized and biosynthesized ZnO nanoparticles were nominated as ZnO A NPs and ZnO B NPs respectively.

2. Methodology

2.1. materials.

All the starting raw materials including zinc acetate dihydrate [Zn(CH 3 COO) 2 .2H 2 O, Merck Specialties, India], sodium hydroxide [NaOH, Merck Specialties, India] and absolute ethanol [CH 3 CH 2 OH, Merck Specialties, Germany) were maintained at a high purity level (>99%). However, in the biosynthesis method, another raw material was also used and that was the leaf of Azadirachta indica (Neem leaf).

2.2. Synthesis of ZnO nanoparticles (ZnO A NPs) by sol-gel method

At first, 20 gm Zn(CH 3 COO) 2 .2H 2 O was mixed into 150 ml distilled water and stirred for 20 min at 35 °C to produce a zinc acetate solution. Again, 80 gm NaOH powder was weighed, mixed into 80 ml water and stirred for around 20 min at 35 °C for producing NaOH solution. After mixing both solutions, the titration reaction was performed by the addition of 100 ml ethanol into the drop-wise manner accompanied by vigorous stirring. The stirring was continued for around 90 min to complete the reaction for obtaining a gel-like product. Then the gel was dried at 80 °C overnight and calcined in an oven at 250 °C for 4 h. Finally, ZnO nanoparticles were prepared. However, the overall chemical reaction for the preparation of ZnO nanoparticles by using NaOH can be expressed as:

2.3. Synthesis of ZnO nanoparticles (ZnO B NPs) by biosynthesis method

At first, the neem (A. Indica) leaves were collected from the Azadirachta Indica trees on the campus of Rajshahi University of Engineering and Technology, Bangladesh. After washing with distilled water, the leaves were dried into a dryer for 24 h. Then 20 gm dried leaves were smashed and mixed with 50 ml distilled water. After that, the mixture was stirred by a magnetic stirrer and heated at 60 °C for 1 h. As the mixture displayed a yellow color, it was filtered using the Whatman TM filter paper. However, the extract solution was used for further preparation of ZnO nanoparticles. The overall process for the preparation of Neem leaf extract is stereotyped in figure 1 .

Figure 1.  Process flow diagram for the preparation of Neem leaf extract.

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The next step included the preparation of the zinc acetate solution. For this, 21.94 gm Zn(CH 3 COO) 2 .2H 2 O was mixed into 50 ml water and stirred for 20 min at 35 °C. Similarly, in order to prepare a NaOH solution, 4 gm NaOH powder was added into 50 ml distilled water and simultaneously stirred for 20 min at 35 °C. Both solutions were then mixed by vigorous stirring. During this stirring process, the neem leaf extract was drop-wise mixed with the solution. As the addition of neem leaf continued, white precipitation of nanoparticles appeared. Then the solution was filtered and the filtered product was dried at 80 °C for 4 h. After that, the dried powder was calcined at 250 °C for 4 h and grounded to obtain the desired ZnO nanoparticles.

2.4. Characterization of ZnO NPs

X-ray diffraction was performed for structural analysis employing 40 kV-40 ma (scanning step of 0.02°) and Cu- K α radiation having wavelengths of K α 1  = 1.54060 Å, K α 2  = 1.54439 Å (Bruker Advance D8, Germany). Morphological characterization was accomplished by scanning electron microscopy (ZEISS EVO 18, UK). The optical properties were determined through UV–vis spectroscopy (SHIMADZU UV/Vis-1650 PC, Japan) into a range of 200–800 nm.

2.5. Antibacterial analysis of ZnO NPs

Escherichia coli bacteria were mainly involved in the determination of the antibacterial performance of ZnO NPs. Initially, the bacteria was stock-cultured in brain heart infusion (BHI) growth medium at −20 °C. Around 3 ml of BHI broth was added to 300 ml of stock-culture and preserved the culture overnight at 36 °C ± 1 °C for 24 h. After 24 h of incubation, dilution of the bacterial suspension (inoculum) was accomplished by using sterile saline. To indicate the bacterial growth during the test, a solution of 2-(4-iodophenyl)−3-(4-nitrophenyl)−5-phenyltetrazolium chloride (INT) in ethanol was added to the bacterial inoculum. Then the inoculum was distributed on a Mueller Hinton Agar Petri Dish in a consistent manner. After that, ZnO A NPs and ZnO B NPs were placed into the wells (prepared by cutting the agar gel) and the systems were preserved at 36 °C ± 1 °C for 24 h to allow successive incubation. After 24 h, the growth of bacteria was monitored and finally, the zone of inhibition for bacterial growth was determined in mm scale.

2.6. Photocatalytic analysis of ZnO NPs

The photocatalytic analysis was performed by monitoring the degradation of Methylene Blue (MB) dye due to ZnO NPs under the influence of UV radiation (having intensity ∼120 μ W cm −2 and wavelength ∼300–400 nm). At first, 5 gm NPs were added into MB solution and mixed properly. The mixture was placed in the dark for 2 h and then irradiated with UV rays with subsequent stirring action and at a variation of time (0, 40, 80, 120, 160, 200 min). The absorbance of the mixture was measured by UV–vis spectroscopy (SHIMADZU UV/Vis-1650 PC, Japan). The efficiency of photodegradation was measured by the following equation:

Where C 0 is the absorption of MB solution before the addition of ZnO NPs and C 1 is the absorption of the mixture solution with respect to time t.

ESR (electron spin resonance) analysis was performed using the EPR spectrometer (Bruker EMX MicroX, Germany) for the identification of the major factor that provides effective photocatalytic performance. During this characterization, DMPO (5,5-dimethyl-1-pyrroline-N-oxide) was used as a spin-trapped reagent in methanol and aqueous state. Moreover, the analysis was performed both in the presence and absence of light irradiation.

3. Results and discussion

3.1. effect analysis of neem leaf extract.

Neem leaf extract contains various phytochemicals such as flavones, quinines, organic acids, aldehyde and ketones which act as reducing agents and significantly reduces the particle sizes. After the successive reduction of particle sizes, the NPs are also affected by the terpenoids. Because of the interaction between the terpenoids and the ZnO NPs become stabilized as terpenoids are effective capping and stabilizing agents. The corresponding mechanism is graphically abstracted into figure 2 . Moreover, the possible seven types of terpenoids that are present in Neem leaf extract are stereotyped in figure 3 .

Figure 2.  Schematic representation of the mechanism of size reduction and stabilization of ZnO NPs during the biosynthesis fabrication scheme using Neem leaf extract.

Figure 3.  Chemical structures of different types of terpenoids subsisting in the Neem leaf extract.

3.2. X-ray diffraction analysis

Figure 4 represents the corresponding X-ray diffraction patterns of ZnO nanoparticles synthesized by sol-gel and bio-synthesis schemes respectively. The intense peaks at the crystal faces (100), (002), (101), (102), (110) assure the emergence of hexagonal wurtzite structure (as shown in figure 5 ) which belong to the space group of P6 3mc (JCPDS card no. 36-1451) [ 18 ]. The bio-synthesized ZnO nano-particles show more acute diffraction peak value introducing the appearance of the high percentage of crystalline phases. In addition, no impurity phases are present in the samples.

Figure 4.  XRD patterns of ZnO A and ZnO B NPs.

Figure 5.  Schematic wurtzite crystal structure of ZnO NPs.

However, considering the most severe diffraction peak (101), the crystallite size (D) can be calculated in accordance with the Debye Scherer formula [ 19 ]:

Hither, β is the Full Width at Half Maxima of the corresponding peak, k is a dimensionless shape factor (∼0.94), while λ is the wavelength of Cu K α radiation (1.54 Å) and ϴ is the Bragg angle. D is mainly the mean size of the ordered domains which is considered to be equal to the particle size (applicable for only particles less than 100 nm). So, the average particle size of ZnO A NPs and ZnO B NPs is 33.20 nm and 25.95 nm respectively [ 19 ]. Again, there remains an inverse relationship between the β and the D which means that narrower peaks are resulted due to larger particles while broader particles are obtained because of smaller particles. The ZnO NPs showed a good agreement with this statement.

Since the crystallite size can be further employed for the determination of defect concentration within the specimen which is designated as the dislocation density ( δ ) and the leading formulae is adopted for this purpose [ 20 ]:

From the exploration of diffraction data, the lattice constant (a & c), inter-planar spacing (d) and unit cell volume (V) of the specimens (table 1 ) can also be enumerated by utilizing the following formulas respectively [ 21 ]:

Where, h, k, l belong to Miller indices.

Table 1.   Structural information on ZnO A and ZnO B NPs.

Besides, the lengthening of the stricture (L) between Zn and O can be enumerated by the following equation [ 20 ]:

Where u corresponds to parameterized constant belonging to wurtzite structure and can be expressed as:

In accordance with the Williamson-Hall proposition, the lattice strain was calculated by adopting the undermentioned equation [ 20 ]:

Figure 6.  W-H plot of (a) ZnO A NPs and (b) ZnO B NPs for the measurement of lattice strain.

3.3. Morphological analysis

Figures 7 (a) and (b) shows the scanning electron micrographs of ZnO A and ZnO B NPs respectively. From the previous section, we have learned that the average particle size of ZnO B NPs (25.97 nm) is smaller than that of ZnO A NPs (33.20 nm). This can be also caused due to the presence of terpenoids in the Neem leaf extract. The terpenoid act not only as a stabilizing agent but also as a powerful reducing agent that interacts with ZnO NPs and reduces its size significantly [ 8 , 17 ]. Moreover, the maximum particles of ZnO A NPs remain between the range of 15 nm to 68 nm, whereas for ZnO B NPs the range lies from 10 nm to 70 nm.

Figure 7.  SEM micrographs of (a) ZnO A NPs and (b) ZnO B NPs.

3.4. Antibacterial activity

Antibacterial activity of ZnO A NPs and ZnO B NPs was analyzed by adopting the agar well diffusion method using Escherichia coli O157: H7 as the bacterial medium. Generally, there involve three mechanisms behind the interaction between the bacteria and the NPs. The first one involves the formation of extremely active hydroxyls and the second one involves the deposition of NPs on the bacteria surface. In addition, for the last one, the NPs accumulates in the cytoplasm or in the periplasmic region of bacteria cell which disrupts the cellular operations and simultaneously disorganizes the membrane. However, in consideration of E. coli , ZnO NPs firstly disorganize the membrane of E. coli and enters into the cytoplasmic region. Positioning themselves into the cytoplasm, the NPs neutralizes the respiratory enzymes and increases the emersion of cytoplasmic contents into the outward direction which impairs the membrane and finally kills the E. coli bacteria resulting in a zone of inhibition of bacterial growth around itself [ 3 , 23 ].

From figure 8 , it is observed that the zone of inhibition of bacterial growth due to ZnO A NPs is different from the zone of inhibition that is caused by ZnO B NPs. However, ZnO B NPs introduce a higher zone of inhibition than ZnO A nanoparticles and the measurements of the inhibition zone of bacterial growth are tabulated in table 2 . According to Krishna R Rangupathi, the antibacterial activity of nanoparticles is a size-dependent property and the property enhances with the reduction of particle size [ 23 ]. As the ZnO B NPs have smaller particle size as well as higher surface area, they show more antibacterial potential than that of ZnO A NPs [ 2 ].

Figure 8.  Antibacterial analysis of ZnO NPs showing the zone of inhibition of the growth of Escherichia coli O157: H7.

Table 2.   Antibacterial measurements of ZnO A NPs and ZnO B NPs.

3.5. Photocatalytic activity

Figure 9.  Degradation mechanism of MB dye by ZnO NPs under the influence of UV irradiation.

However, the corresponding reactions in the photodegradation scheme can be summarized as below [ 24 , 25 ]:

Figure 11 displays the discoloration of MB dye due to the photocatalytic action of ZnO NPs at different times (0, 40 and 120 min). However, figures 12 (a) and (b) illustrates the absorption spectra of MB dye as a function of wavelength under the influence of UV radiation at a variation of time i.e. 0, 40, 80, 120, 160, 200 min. From the graph, it is observed that the absorption rate of MB containing ZnO B NPs decreases more rapidly than that of ZnO A NPs. Moreover, the degradation efficiency ( η ) of ZnO NPs (biosynthesized and sol-gel synthesized) with respect to time is illustrated in figure 13 . The degradation of MB for sol-gel synthesized ZnO are 35.3%, 45.7%, 56.1% 62.4%, 68.9% at 40, 80, 120, 160 and 200 min respectively. Again, the values for biosynthesized ZnO are 36.9%, 47.5%, 62.7%, 72.1%, and 80.2% at 40, 80, 120, 160 and 200 min respectively. So, MB dye degraded more rapidly in the presence of ZnO B NPs backing the reason for smaller particle sizes than that of ZnO A NPs. As the particles become smaller, the active surface area for the photocatalysis increased which results in enhanced degradation of MB [ 26 ]. Moreover, there remain terpenoids in the neem leaf extract which stabilizes the nanoparticles by capping themselves which also causes in the increment of photocatalytic action [ 27 ].

Figure 11.  Visual inspection of the degradation phenomenon of MB dye by ZnO NPs.

Figure 12.  Absorption spectrum of (a) ZnO A NPs and (b) ZnO B NPs as a function of wavelength at 0, 40, 80, 120, 160, 200 min.

Figure 13.  The degradation efficiency of ZnO NPs for methylene blue dye with respect to time.

3.6. Optical analysis

Figures 14 (a) and (b) displays the room temperature absorption spectrum of ZnO nanoparticles fabricated by sol-gel and biosynthesis methods correspondingly. Here, the absorption wavelengths are remaining within the maximum allowable limit of the absorption band of bulk ZnO (∼373 nm). Although the absorption slightly increases up to a wavelength of 363 nm for ZnO A NPs, the maximum incremental value for ZnO B NPs is 356 nm. The slight shift of the absorption peak may be caused due to the variation of particle size and their configuration [ 28 ]. However, this phenomenon results in the presence of a wide range of particle size distribution of ZnO [ 29 ]. Moreover, the redshift of ZnO A NPs compared to ZnO B NPs corresponds to the formation of agglomeration in the specimens significantly. Furthermore, in accordance with Gunanlan Sangeetha et al the shifting of absorption band to the higher wavelength as well as higher energy was associated with the increment of the size of nanoparticles [ 30 ]. Moreover, considering the direct interband transition between the valence band and the conduction band, the absorption band gap energy was measured by adopting the following Tauc's formula [ 31 ]:

Where A is an energy-independent constant, α is the absorption coefficient, h υ is for the photon energy, and E g is the optical band gap energy. The E g of the ZnO NPs was obtained from the ( α h υ ) 2 versus h υ plot (as shown in the inset of figures 14 (a) and (b). Where the extrapolation of the linear segment of the graph to (α h υ ) 2  = 0 provides the value of E g for ZnO NPs. It is observed that the optical band gap energy of ZnO B NPs (3.25 eV) is higher than that of ZnO A NPs (3.23 eV). This incremental phenomenon is mainly attributed to the quantum confinement effect. According to this theory, as the particle size decreases, the electrons in the valence band and the holes in the conduction band confine themselves within a space having a dimension of the de Broglie wavelength. However, this confinement influences the quantization of the energy and the momentum of the corresponding carriers and also enhances the optical transition energy between the valence band and the conduction band resulting in a broad band gap [ 32 ].

Figure 14.  Absorption spectra of (a) ZnO A NPs and (b) ZnO B NPs (inset shows ( α h υ ) 2 versus h υ plot for the determination of band gap energy.

Figure 15 displays the UV visible transmittance spectrum of ZnO A NPs and ZnO B NPs. Here, the transparency of ZnO B NPs is greater than that of ZnO due to the reduced particle size of ZnO B NPs. From the research of Takuya Tsuzuki, it is clear that smaller particles are capable to show higher transparency at the visible range of spectrum [ 33 ]. However, the UV blocking characteristics are almost similar for each of the variants of NPs.

Figure 15.  Typical transmittance spectra of ZnO NPs.

4. Conclusion

In summary, ZnO NPs were synthesized by two different methods i.e., sol-gel and biosynthesis method. The green synthesis of ZnO NPs allows avoiding the toxic chemical agents that are used in the sol-gel method for the size reduction. However, the Neem leaf extract possesses some phytochemicals which not only performs in the reduction of the particle sizes but also provide sufficient stabilization. Although, the average particle size of ZnO B NPs (25.97 nm) was smaller than that of ZnO A NPs (33.20 nm), the optical band gap energy of ZnO B NPs was higher than that of ZnO A NPs due to the quantum confinement effect. In addition, the antibacterial and photocatalytic properties of ZnO B NPs were greater than that of ZnO A NPs. Where, the zone of inhibition of bacterial growth for ZnO B NPs was 14.5 mm and for ZnO A NPs, it was 9.3 mm. Moreover, the degradation efficiency of ZnO B NPs at 200 min was 80% while for ZnO A NPs, the corresponding efficiency was 68%. Again, from the ESR analysis, it was proved that the OH · radicals were the main contributing factor for the degradation of MB dye. So, based on the comparison between the properties of the two variants, it is concluded that the biosynthesis method shows more effectiveness than the sol-gel method for the synthesis of ZnO NPs.

Acknowledgments

The authors are grateful to Rajshahi University of Engineering & Technology (RUET) for providing the opportunity to perform various tests. Special thanks go to Tasmia Zaman, Assistant Professor, Department of Glass & Ceramic Engineering, Rajshahi University of Engineering & Technology, Bangladesh for her cordial assistance.

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• Published: 03 June 2020

Green route to synthesize Zinc Oxide Nanoparticles using leaf extracts of Cassia fistula and Melia azadarach and their antibacterial potential

• Minha Naseer 1 ,
• Usman Aslam   ORCID: orcid.org/0000-0001-8145-8360 2 ,
• Bushra Khalid 3 , 4 &
• Bin Chen   ORCID: orcid.org/0000-0002-0925-9209 5 , 6  

Scientific Reports volume  10 , Article number:  9055 ( 2020 ) Cite this article

• Antimicrobial resistance
• Nanoparticles

Development of plant based nanoparticles has many advantages over conventional physico-chemical methods and has various applications in medicine and biology. In present study, zinc oxide (ZnO) nanoparticles (NPs) were synthesized using leaf extracts of two medicinal plants Cassia fistula and Melia azadarach . 0.01 M zinc acetate dihydrate was used as a precursor in leaf extracts of respective plants for NPs synthesis. The structural and optical properties of NPs were investigated by X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, scanning electron microscope (SEM), ultraviolet-visible spectrophotometer (UV-Vis) and dynamic light scattering (DLS). The antibacterial potential of ZnO NPs was examined by paper disc diffusion method against two clinical strains of Escherichia coli ( E. coli ) and Staphylococcus aureus ( S. aureus ) based on the zone of inhibition and minimal inhibitory indices (MIC). Change in color of the reaction mixture from brown to white indicated the formation of ZnO NPs. UV peaks at 320 nm and 324 nm, and XRD pattern matching that of JCPDS card for ZnO confirmed the presence of pure ZnO NPs. FTIR further confirmed the presence of bioactive functional groups involved in the reduction of bulk zinc acetate to ZnO NPs. SEM analysis displayed the shape of NPs to be spherical whereas DLS showed their size range from 3 to 68 nm. The C. fistula and M. azadarach mediated ZnO NPs showed strong antimicrobial activity against clinical pathogens compared to standard drugs, suggesting that plant based synthesis of NPs can be an excellent strategy to develop versatile and eco-friendly biomedical products.

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Introduction.

Plant mediated synthesis of nanoparticles (NPs) is a revolutionary technique that has wide range of applications in agriculture, food industry and medicine. NPs synthesized via conventional methods have limited uses in clinical domain due to their toxicity. Due to the physio-chemical properties of plant based NPs, this method also offer an added advantage of increased life span of NPs that overcome the limitations of conventional chemical and physical methods of NPs synthesis 1 , 2 , 3 . Plants possess rich genetic variability with respect to number of biomolecules and metabolites like proteins, vitamins, coenzymes based intermediates, phenols, flavonoids and carbohydrates. These plant metabolites contain hydroxyl, carbonyl, and amine functional groups that react with metal ions and reduce their size into nano range. More specifically, flavonoids contain several functional groups and it is believed that -OH group of flavonoids is mainly considered responsible for the reduction of metal ions into NPs 4 . These molecules not only help in bioreduction of the ions to the nano scale size, but they also play a pivotal role in the capping of the nanoparticles which is important for stability and biocompatibility 5 . Reducing agents such as phenolic compounds, sterols and alkaloids can reduce metal ions into NPs in a single reaction 6 .

The type and nature of the metal used for NPs biosynthesis mainly determines the NPs end use industry. Several metals such as silver (Ag), copper (Cu), gold (Au) and many others have been widely used for the biosynthesis of NPs using plant extracts of various plant species 7 , 8 , 9 . However their higher toxicity to animals and humans pose a serious limitation for use in medical industry. ZnO is an inorganic compound which occurs rarely in nature. It is generally found in crystalline form. Naturally occurring ZnO has manganese impurities that give it a typical red or orange color appearance 10 . When purified, ZnO appears as white crystalline powder which is nearly insoluble in water. Due to their low toxicity and size dependent properties, ZnO NPs have been widely used for various applications in textiles, cosmetics, diagnostics and even in micro-electronics. Because ZnO is generally recognized as safe (GRAS) and exhibits antimicrobial properties, ZnO NPs hold greater potential to treat infectious diseases in humans and animals 11 .

ZnO has been found to be potentially useful and efficient than other metals for biosynthesis of NPs for clinical purposes. Several studies have demonstrated the synthesis of ZnO NPs using different plant extracts. For example, flower extract of the medicinal plant Cassia auriculata 12 and leaf extract of Hibiscus rosasinensi 13 were used as reducing agents for zinc nitrate to synthesize ZnO NPs.

Plant type or source species from which plant extract used for NPs synthesis also affects the size of NPs. For example, when Olea europea leaf extract was used to synthesize ZnO nano sheets, it ranged from 18–30 nm in size 14 . However, when Aloe barbadensis 15 and Ocimum tenuiflorum 11 were used as reducing agent for the green synthesis of ZnO nanoparticles, the average nanoparticle sizes were 25–40 nm and 13.86 nm respectively. Recently various reports have also demonstrated the antimicrobial activity of ZnO NPs. For example, ZnO NPs synthesized by using leaf extracts of Passiflora caerulea , Scadoxus multiflorus and Camellia sinensis showed strong antimicrobial efficacy against Klebsiella pneumonia , Aspergillus spp., and Staphylococcus aureus and Pseudomonas aeruginosa respectively 16 , 17 , 18 , suggesting that medicinal plant extract mediated synthesis of ZnO NPs can be very useful for medical industry.

Cassia fistula commonly known as Golden Shower or Amaltas is a deciduous tree with medicinal importance, native to Pakistan and India and found as an exotic species in Egypt, Australia, Ghana, Mexico, and Zimbabwe. It belongs to the family Fabaceae . It produces shiny green leaves which are about 30–40 cm long, pinnate in shape and arranged in alternate fashion on the terminal branches 19 . Leaves of C. fistula contain a wide variety of antioxidants for example; terpenoids, flavonoids, alkaloids, phenolic compounds, tannins, saponins, anthocyanosides, carbohydrates, proteins, steroids, cardiac glycosides and phlobatannins 20 .

Similarly, Melia azadarach commonly known as Cape Lilac and locally as Bakain belongs to the family Meliaceae . It is native to Southeast Asia and found naturally in most of the tropical and subtropical countries. This plant is locally famous for its anti-microbial, anti-inflammatory and anti-cancer activities and often used to treat stomach pains and parasitic infections. It produces dense array of dark green leaves which are short stalked and arranged in alternate pattern on terminal branches. Fruits are yellow colored, smooth and fleshy berries. M. azadarach is naturally enriched in phytochemicals. It is endowed with alkaloids, sterols, glycosides, flavonoids, limonoids, fixed oil and fats, phenolic compounds, tannins, saponins, gum and mucilages, triterpenes, azadirachitin, nimbin, melianoninol, melianol, meliandiol, vanillin, meliacin, quercertin and rutin 21 . Due to the presence of diverse array of these phytochemicals and medicinal properties, C. fistula and M. azedarach hold greater potential for efficient biosynthesis of NPs that can be useful to treat clinical pathogens.

Here, we report a simple and eco-friendly method of ZnO NPs synthesis from the plant extracts of C. fistula and M. azedarach as reducing agents and zinc acetate as precursor for their comparative analysis of antimicrobial potential. This research will increase the potential of usage of plant based NPs in biomedical industry.

Results and Discussion

Optical analysis of zno nps formation.

Adding zinc acetate dihydrate in leaf extracts of C. fistula and M. azedarach leads to physio-chemical changes in the aqueous solution. The most prominent of which is change in the colour of the reaction mixture that can be observed within few minutes. This was considered as an initial signature to formation of NPs. In present study, change of color from yellow to light brown and red to off-white indicated the formation of ZnO NPs in leaf extracts of C. fistula and M. azedarach , respectively. Flavonoides and phenolic compounds are thought to be responsible for Zn ions to ZnO NPs. In a period of few hours, the colour of the solution stopped changing further suggesting the complete bioreduction of ZnO salt into NPs. A clear illustration of change in color of the reaction mixtures due to formation of ZnO NPs has been shown in Fig.  1(A,B) . These results were consistent with the previous reports of color changes in plant based synthesis of ZnO NPs 22 . Temperature is considered an important contributing factor in synthesis of good sized nanoparticles. It is also well established that higher the temperature of reaction process of NPs synthesis, the smaller the size of the NPs 23 , 24 . Therefore, we use a relatively higher temperature of 70 °C for incubating the reactants that leads to the production of very small sized ZnO NPs.

Optical analysis of ZnO NPs. ( A,B ) Color changes indicating formation of ZnO NPs. A) Cassia fistula mediated ZnO NPs. ( B ) Melia azadarach mediated ZnO NPs. ( C,D ) UV-visible absorption spectrum confirming presence of ZnO NPs. ( A ) Cassia fistula mediated ZnO NPs. ( B ) Melia azadarach mediated ZnO NPs.

The synthesis of ZnO NPs was further examined by UV spectrophotometry. Figure  1(C,D) shows the UV peaks recorded by the spectrophotometer. The maximum absorption peak for ZnO NPs synthesized via C. fistula was recorded at 320 nm and with that of M. azadarach at 324 nm that further verified the formation of ZnO NPs. Firstly, these results satisfy standard ZnO absorption pattern because all oxide materials have wide band gaps and tend to have shorter wavelengths. Moreover, if the material is of nanoscale, it tends to have further shorter wavelengths. This notion support the results observed for ZnO NPs here 25 .

Surface morphology of ZnO NPs

The presence of nanoparticles and examination of their structural properties were confirmed by X-ray diffractrometer. C. fistula and M. azedarach associated ZnO NPs showed peaks with 2θ values identified at 31.841°, 34.507°, 36.324°, 47.592°, 56.634°, 66.426°, 67.983°, 69.091°, and 76.987° which are indexed as (100), (002), (101), (102), (110), (103), (112), (201) and (202) planes (Fig.  2A,B ). These peaks were in accordance with those of data card (JCPDS-36-1451). Average crystal size calculated using the Scherrer’s equation ( \(Dp\,of\,ZnO\,NPs=(0.9(1.5406)/0.63(\cos \,36)\) came out to be around 2.72 nm for both C. fistula and M. azedarach associated ZnO NPs that is comparable with the size of good quality NPs in existing reports 26 .

( A,B ) XRD pattern indicating presence of ZnO peaks. ( A ) Cassia fistula mediated ZnO NPs. ( B ) Melia azadarach mediated ZnO NPs. ( C,D ) FTIR pattern indicating the functional groups involved in ZnO NPs synthesis. ( C ) Cassia fistula mediated ZnO NPs. ( D ) Melia azadarach mediated ZnO NPs.

To identify the functional groups associated with the ZnO NPs formation, FTIR spectrometry was performed. Spectral peaks at 683–500 cm −1 and 698–505 cm −1 proposed the formation of ZnO nanoparticles in C. fistula and M. azedarach extracts, respectively (Fig.  2C,D ). Absence of peaks in the region of 3500 and 2500 cm −1 indicated no characteristic OH and N-H stretching of aldehydes. The bands at 1600–1510 cm −1 correspond to amide I and amide II regions arising due to carbonyl stretching in proteins and that of 1400 to 1000 cm −1 correspond to methylene from the proteins in the solution and C-N stretching vibrations of amine. Peaks from 1460–1410 cm −1 suggested C-C stretching vibration of alcohol, carboxylic acid, ether and ester and bands at 946–769 cm −1 demonstrated presence of carboxylic acid and aromatic C-H bending. Although, many changes were not observed at these frequencies but all peaks showed a shift to lower frequency and a decrease in intensity on binding with the nanoparticles. This trend of free carbonyl and NH 2 groups from proteins and amino acid residues indicates that they have ability to bind to a metal and that the proteins could possibly form a layer around the metal for preventing agglomeration and thereby stabilizing the nanoparticles. It is revealed from the FTIR spectra that in fact, the protein molecules present in the leaf extract possibly cause the reduction of metal ions which is in agreement with the previous reports 27 . These findings suggest that not only the OH group of flavonoids but also the protein molecules and their functional groups play important role in bioreduction of salts and capping of NPs.

Dynamic Light Scattering (DLS) measurements showed the average diameters of C. fistula and M. azadarach mediated ZnO NPs (Fig.  3 ). Average diameters of ZnO NPs synthesized from C. fistula and M. azadarach were 68.1 nm and 3.62 nm, respectively. The results demonstrated that the particles synthesized were ultrafine i.e. less than 100 nm in diameter. It clearly depicts that M. azadarach extract was more efficient than C. fistula for synthesizing smaller NPs. It may be attributed to the presence of more variety of phytochemicals in M. azadarach when compared to C. fistula . As it has already been mentioned in the introduction section that M. azadarech possesses complete set of phytochemicals that can be the reason behind higher efficacy of this plant as a reducing agent when compared to C. fistula . In addition, DLS analysis demonstrated that the NPs formed had fairly well-defined dimensions 28 . Smaller the size of the NPs, higher the surface area, thus higher the antimicrobial activity. Generally, bacterial cellular membranes have nanometer size. If the nanoparticles are smaller in size than cell membrane pores, there is more possibility of crossing the cell membrane barrier and thus inhibiting the bacterial growth 29 .

DLS indicating average size of ZnO NPs. ( A ) Cassia fistula mediated ZnO NPs. ( B ) Melia azadarach mediated ZnO NPs.

Figure  4 shows Scanning Electron Microscopy (SEM) images of ZnO NPs synthesized from leaf extracts of C. fistula and M. azadarach . The images were recorded at magnification of 10 µm, 1 µm and 100 nm. Topographical view shows that nanoparticles are more or less spherical in nature, clustered together and surface of the aggregates seems to be rough 30 . SEM images also revealed that NPs derived from both plants are entirely pure and it can be concluded that both the plants have tremendous capability to synthesize ZnO NPs. Shape of NPs plays very crucial role in the effectivity against pathogens. Because spherical NPs tend to be very potent during antibacterial activity owing to their ability to easily penetrate into the cell wall of pathogens 31 , therefore, ZnO NPs syntheized from these two plant species can be of great importance in treating clinical pathogens.

SEM images of ZnO particles showing their morphology at three different resolutions. ( A–C ): Scanning Electron Micrographs of Cassia fistula mediated Zno NPs. ( A ) SEM of Zno NPs captured at 500× magnification. ( B ) SEM of Zno NPs captured at 16,000× magnification. ( C ) SEM of Zno NPs captured at 65,000× magnification. ( D–F ): Scanning Electron Micrographs of Melia azadarach mediated Zno NPs. ( D ) SEM of Zno NPs captured at 800× magnification. ( E ) SEM of Zno NPs captured at 8,000× magnification. ( F ) SEM of Zno NPs captured at 30,000× magnification. Red dotted circles in ( C,F ) indicate the NPs circumference.

Antibacterial activity of ZnO NPs

The bactericidal activities of C. fistula and M. azadarach mediated ZnO NPs were tested against two main clinical pathogens; a (Gram-negative pathogen) E. coli and b (Gram-positive pathogen) S. aureus . Figure  5 illustrates zones of inhibition of E. coli and S. aureus against standard drugs and biosynthesed ZnO NPS at concentrations ranging from 50 µg/mL (10 µL) to 1000 µg/mL (200 µL). The mean values of zone of inhibition (mm) of three replicates are presented in (Table  1 ). Comparison between standard antibiotics and biosynthesed NPs showed strong antibacterial effect of NPs as compared to standard drugs (Table  2 ). In E. coli , zone of inhibition of standard drugs ranged from 15–20 mm while that of ZnO NPs was 16–40 mm. S. aureus was resistant to a variety of standard drugs and zone of inhibition for rest of the standard drugs was ranged from 4–13 mm while that of ZnO NPs was 14–37 mm in range. (Table  3 ) shows zones of inhibition of various standard drugs and standard drug potency according to WHO standards.

Resistance level of two clinical pathogens against (i) standard drugs, (ii) ZnO NPs 10 µL, 50 µL and (iii) ZnO NPs 100 µL, 200 µL. ( A ) Inhibition zones of ZnO NPs against E. coli growth. ( B ) Inhibition zones of ZnO NPs against S. aureus growth. Lower panel in both part A and B illustrates the labelling of petri plates.

Both the E. coli and S. aureus showed minimum inhibitory concentration (MIC) at 10 µL for the synthesized ZnO NPs. Furthermore, as the concentration of NPs increased so did the zone of inhibition. It is evident from the recordeded images and statistical data that zone of inhibition of C. fistula mediated ZnO NPs was more significant against E. coli ( ∼ 44 mm) as compared to S. aureus (Fig.  5 , Table  2 ). The mild inhibitory effect of C. fistula mediated ZnO NPs on S. aureus when compared to E. coli can be attributed to the differences in membrane strutures of Gram-positive and Gram-negative bacteria. The most disntinctive feature of Gram-positive bacterium is the thickness of cell wall due to the prescence of peptidoglycan layer. It has also been reported that ZnO NPs may damge bacterial cell membrane resulting lysis of intracellular contents and ultimately proved to be lethal for the bacterial cell 32 . Lower efficacy of C. fistula mediated ZnO NPs against S. aureus compared to the Gram-negative species might be due to the resistance of cell wall in Gram-positve species 33 . By contrast, the zone of inhibition of M. azadarach mediated ZnO NPs was compareable against both the pathogens. However, it is important to note that the zone of inhibition of M. azadarch mediated ZnO NPs was significantly greater in comparison to C. fistula mediated ZnO NPs against S. aureus (Fig.  5 , Table  2 ). These results suggest that the use of M. azadarch mediated synthesis of ZnO NPs can be more efficient against Gram-positive pathogens like S. aureus . This might be due to the presence of higher number of phenolic compounds and rare secondary metabolites such as nimbinene, meliacin, quercertin and rutin in M. azadarch .

As a schematic layout of this whole study, a model has been given in Fig.  6 that shows the graphical representation of the synthesis of ZnO NPs using leaf extarcts of C. fistula and M. azadarach as reducing agents and zinc acetate as a precursor salt.

Schematic model of ZnO NP synthesis from the leaf extracts of Cassia fistula and Melia azedarach and their antibacterial activity analysis.

Leaf extracts of C. fistula and M. azadarach showed excellent potential as reducing agents in the formation of NPs. Structural and optical studies conducted using UV, FTIR, XRD, DLS and SEM analysis confirmed the formation of efficient ZnO NPs. Antibacterial analysis revealed that ZnO NPs synthesized from leaf extracts exhibited significant capability of inhibition against the clinical pathogens when compared to traditional drugs. Moreover, some plant extratcs are more effective than that of others in synthesizing NPs and biological activities due to their diverse biochemical compositions. In conclusion, synthesis of NPs using extratcs of medicinal plants can have useful medicinal applciations in treatment of numerous human infectious pathogens. However, further studies will be required to validate the efficacy of these NPs in medical applications and their capacity to overcome the risks associated with conventional drugs.

Synthesis of Nanoparticles

All the glassware were autoclaved before use. To prepare leaf extract, fresh leaves of C. fistula and M. azadarach were thoroughly washed with tap water followed by distilled water (d.H 2 O) to remove any contamination. The leaves were air dried for a week at room temperature ( ∼ 37°C). About 5 g of leaves from each of C. fistula and M. azadarach were ground to fine powder with the help of pestle and mortar. This powder was mixed in 500 mL of d.H 2 O and then heated at 70°C for 30 minutes. The mixture was filtered first by muslin cloth and then using Whatman filter paper No.1. As a result, pale yellow and red colored solutions were obtained as leaf extracts of C. fistula and M. azadarach respectively which were stored at 4 °C.

0.01 M zinc acetate dihydrate (Zn (C 2 H 3 O 2 ) 2 .2H 2 O) solution was prepared in d.H 2 O. For synthesis of ZnO nanoparticles, 95 mL of 0.01 M zinc acetate dihydrate (Zn (C 2 H 3 O 2 ) 2 .2H 2 O) solution was mixed separately with 5 mL plant extract of each of C. fistula and M. azadarach in individual 250 mL flasks. These mixtures were incubated at 70°C for 1 hour with continuous shaking at 150 rpm. This led to the settlement of bio-reduced salt at the bottom of the flask which appeared as white precipitate. The supernatant was decanted and powdery precipitate was transferred to 1.5 mL centrifuge tubes. Both the samples were subjected to washing with d.H 2 O by centrifugation at 3000 rpm for 30 minutes. Washing step was repeated thrice to ensure removal of impurities 22 .

Characterization of NPs

Optical Spectroscopy . To measure the optical parameters, ZnO synthesized nanoparticles were dispersed in d.H 2 O. The absorption spectrum of synthesized NPs was measured using UV–VIS-NIR spectrophotometer (UV-1601, Shimadzu, Japan) in wavelength range between 200–800 nm. The d.H 2 O was used as a reference. Energy gap or band gap was calculated using the following equation

where Eg is the bulk band expressed in eV. Lambda ( 𝜆 ) is peak absorbance wavelength in nm. Therefore, the energy gap for ZnO ranges from 4.27–3.87 eV 34 .

FTIR Analysis . The surface chemistry of NPs was analyzed by FTIR spectroscopy. The functional groups attached to the surface of NPs were detected in the range of 4000–400 nm. The samples were prepared by dispersing the ZnO NPs uniformly in a matrix of dry KBr which was then compressed to form a transparent disc. KBr pellet was used as a standard 35 .

XRD Analysis . X-ray diffractrometer (PAN analytical X-Pert PRO) was used to study the surface morphology, size and crystalline nature of ZnO NPs. The diffraction pattern was obtained using CuKα radiation with wavelength of λ = 1.541 A°. A thin film of the sample was made by putting a small amount of sample on a glass plate for XRD studies. The scanning was done in 2θ value range of 4° to 80° at 0.02 min −1 and 1 second time constant. The instrument was operated at a current of 30 mA and voltage of 40 kV. Scherrer’s equation was used to calculate the average grain size of synthesized NPs which is as under

where D represents the crystallite size, λ stands for the wavelength (1.5406 Å for Cu Kα), β symbolizes the full-width at half-maximum (FWHM) of main intensity peak after subtraction of the equipment broadening and θ is used as a diffraction angle in radians.

DLS Analysis . The particle size distribution of the samples was obtained through Particle Size Analyzer (Zetasizer Ver. 7.11 Malvern). The liquid samples of ZnO NPs was diluted ten times using Milli-Q water, centrifuged and then transferred to cuvette for analysis. The zeta potential of ZnO NPS was determined in water as dispersant.

SEM Imaging . The samples of ZnO NPs were dispersed in methanol (evaporating solvent) at a concentration of 1 mg/20 mL. A single drop of aqueous solution of ZnO NPs was placed on the carbon coated grid to prepare a thin film. Extra solution was removed with the help of blotting paper and the grid was allowed to dry under mercury lamp for around five minutes. The morphological measurements of the ZnO NPs samples were recorded with field emission scanning electron microscope (JEOL, Model: JSM-7600F) in the range of 0.1 nm to 10,000 nm. The data collected from all techniques was analyzed in Origin software version 9.1.

Antimicrobial analysis

To check the bactericidal potential of the NPs, pure cultures of Escherichia coli (EPEC-A (P16), and Staphylococcus aureus [(MRSA belonging to clonal complex 8 (CC8) and sequence type 239 (ST239)] were obtained from the Department of Microbiology, Pakistan Institute of Medical Sciences (PIMS), Islamabad. Disc diffusion method was used to carry out the antibacterial assay of NPs on Muller Hinton Agar (MHA) medium containing petri plates. Contamination test was carried out by incubating the plates over night at room temperature. After confirmation of no contamination, bacterial cultures were streaked on to these MHA plates.

Stock solution of NPs was prepared in d.H 2 O at a concentration of 5 mg/mL. Further, four working dilutions i.e. 50 µg/mL (10 µL), 250 µg/mL (50 µL), 500 µg/mL (100 µL) and 1000 µg/mL (200 µL) were made to find out minimum inhibitory concentration (MIC). The Minimum Inhibitory Concentration (MIC) of the ZnO NPs was determined based on batch cultures containing varying concentrations of ZnO NPs in suspension (10–200 µg/mL). Bacterial concentrations were determined by measuring optical density (OD) at 600 nm.

To examine the bactericidal effect of NPs on clinical strains, approximately 10 8 CFU of each strain was cultured on nutrient agar plates. Following disc diffusion method, the sterile discs were dipped in ZnO nanoparticles solution at varying concentrations from 50 µg/mL to 1000 µg/mL. Discs were placed onto the MHA plates and incubated at 37 °C. Control samples were prepared by placing standard medicine discs onto MHA plates containing bacterial isolates. Standard medicines used for E. coli were Ceftazidime, Imipenem, Cefoperazone, Amoxicillin, and Cefixime, whereas, Erythromycin, Gentamycin, Vancomycin, Chloramphenicol, Lanzolid were used for S. aureus . Mean values of inhibitory zone diameter were recorded in three experimental repeats. The average values of inhibition zones were calculated as Mean ± Standard Deviations. The data was statistically analyzed using Origin software version 9.1 36 .

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Acknowledgements

This work was supported by the International Partnership Program of the Chinese Academy of Sciences [grant number 134111KYSB20180021), the National Natural Science Foundation of China [grant numbers 41590871], and the International Science & Technology Cooperation Program of China [grant number 2013DFG22820]. The authors highly acknowldege the techinal support for this research from the Department of Microbiology, Pakistan Institute of Medical Sciences (PIMS), Islamabad and Pakistan Institute of Nuclear Science and Technology (PINSTECH), Islamabad, Pakistan.

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Minha Naseer

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Usman Aslam

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The Abdus Salam International Centre for Theoretical Physics, Trieste, Italy

Institute of Atmospheric Physics, Chinese Academy of Sciences, Beijing, 100029, China

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Naseer, M., Aslam, U., Khalid, B. et al. Green route to synthesize Zinc Oxide Nanoparticles using leaf extracts of Cassia fistula and Melia azadarach and their antibacterial potential. Sci Rep 10 , 9055 (2020). https://doi.org/10.1038/s41598-020-65949-3

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DOI : https://doi.org/10.1038/s41598-020-65949-3

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Zinc oxide nanoparticles: synthesis, characterization, modification, and applications in food and agriculture.

Graphical Abstract

1. Introduction

2. structure, 3. preparation method, 3.1. conventional synthesis methods, 3.2. biological/green synthesis methods, 3.3. physical synthesis methods, 3.4. a non-conventional method, 4. modifications, 5. common tools and techniques for characterization, 5.1. uv-vis spectrophotometer (uv-vis), 5.2. x-ray diffractometer (xrd), 5.3. fourier transform infrared spectroscopy (ft-ir), 5.4. atomic force microscopy (afm), 5.5. scanning electron microscopy (sem), 5.6. transmission electron microscopy (tem), 5.7. x-ray photoelectron spectroscopy (xps), 6. morphological impacts, 7. advantages and possible risk, 7.1. advantages, 7.2. possible risk, 7.3. regulations, 8. applications, 8.1. role in agriculture, 8.2. as antimicrobial agent against food-borne pathogens, 8.3. role in food processing and storage, 8.4. role in food packaging, 8.5. role in food flavor, 9. summary and future perspectives, author contributions, data availability statement, conflicts of interest.

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Zhou, X.-Q.; Hayat, Z.; Zhang, D.-D.; Li, M.-Y.; Hu, S.; Wu, Q.; Cao, Y.-F.; Yuan, Y. Zinc Oxide Nanoparticles: Synthesis, Characterization, Modification, and Applications in Food and Agriculture. Processes 2023 , 11 , 1193. https://doi.org/10.3390/pr11041193

Zhou X-Q, Hayat Z, Zhang D-D, Li M-Y, Hu S, Wu Q, Cao Y-F, Yuan Y. Zinc Oxide Nanoparticles: Synthesis, Characterization, Modification, and Applications in Food and Agriculture. Processes . 2023; 11(4):1193. https://doi.org/10.3390/pr11041193

Zhou, Xian-Qing, Zakir Hayat, Dong-Dong Zhang, Meng-Yao Li, Si Hu, Qiong Wu, Yu-Fei Cao, and Ying Yuan. 2023. "Zinc Oxide Nanoparticles: Synthesis, Characterization, Modification, and Applications in Food and Agriculture" Processes 11, no. 4: 1193. https://doi.org/10.3390/pr11041193

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Synthesis and Optical Properties of Zinc Oxide Nanoparticles grown on Sn-coated Silicon Substrate by Thermal Evaporation Method. Outline. Introduction ZnO Vs. GaN Experimental details Results and discussion Surface morphology Crystalline structure Optical properties

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Effect of ZnO Nanoparticles Dispersed in Liquid Crystalline Alkoxy Benzoic Acids and Periodic Noise Reduction using Freq

In the present work, the synthesis and characterization are carried out on liquid crystalline compounds p-n-alkoxy benzoic acids namely p-n-octyloxy benzoic acid (8OBA) and p-n-do decyloxy benzoic acid (12OBA) compounds with 0.5 wt% ZnO nanoparticle dispersion. The differential scanning calorimetry (DSC) technique is used to measure the phase transition temperatures. Further characterization is carried out by various spectroscopic techniques like UV-visible spectroscopy (UV), scanning electron microscopy studies (SEM) and Fourier transform infra-red spectroscopy (FTIR). Textural determinations of the synthesized compounds were recorded by using polarizing optical microscope (POM) connected with hot stage and camera. The results showed that the dispersion of ZnO nanoparticles in 8OBA and 12OBA exhibited NC phases as same as the pure compounds with reduced clearing temperature as expected.

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Many sunscreens these days contain zinc oxide nanoparticles which have been rumored to cause DNA toxicity.

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ZnO nanostructured materials and their potential applications: progress, challenges and perspectives

First published on 9th March 2022

Extensive research in nanotechnology has been conducted to investigate new behaviours and properties of materials with nanoscale dimensions. ZnO NPs owing to their distinct physical and chemical properties have gained considerable importance and are hence investigated to a detailed degree for exploitation of these properties. This communication, at the outset, elaborates the various chemical methods of preparation of ZnO NPs, viz. , the mechanochemical process, controlled precipitation, sol–gel method, vapour transport method, solvothermal and hydrothermal methods, and methods using emulsion and micro-emulsion environments. The paper further describes the green methods employing the use of plant extracts, in particular, for the synthesis of ZnO NPs. The modifications of ZnO with organic (carboxylic acid, silanes) and inorganic (metal oxides) compounds and polymer matrices have then been described. The multitudinous applications of ZnO NPs across a variety of fields such as the rubber industry, pharmaceutical industry, cosmetics, textile industry, opto-electronics and agriculture have been presented. Elaborative narratives on the photocatalytic and a variety of biomedical applications of ZnO have also been included. The ecotoxic impacts of ZnO NPs have additionally been briefly highlighted. Finally, efforts have been made to examine the current challenges and future scope of the synthetic modes and applications of ZnO NPs.

1. Introduction

ZnO has a slew of unique chemical and physical properties, viz. , high chemical stability, high electrochemical coupling coefficient, broad range of radiation absorption and high photostability, which make it among all metal oxides a key technological material and confer upon it its wide applications in varied fields. ZnO is categorized as a group II–VI semiconductor in materials science because zinc belongs to the 2 nd group while oxygen belongs to the 6 th group of the periodic table. Its covalence is on the borderline demarcating ionic and covalent semiconductors. Besides, it has good transparency, high electron mobility, an outsized exciton binding energy (60 meV), wide band gap (3.37 eV), 1 strong room temperature luminescence, high thermal and mechanical stability at room temperature, broad range of radiation absorption and high photostability that make ZnO the most favorite multitasking material. 2,3,5,6 As a result of its distinctive optical and electrical properties 4 it is considered to be a possible material in electronic applications, optoelectronic applications and laser technology. ZnO among nano-sized metal oxides has also been further extensively exploited to derive possible benefits from its antimicrobial and antitumor activities. 7 Because of its blocking and absorbing capabilities ZnO finds inclusion in some cosmetic lotions. 8 ZnO can also be used in human medicine as an astringent (for wound healing), and to treat hemorrhoids, eczema and excoriation. 9 ZnO nanoparticles have recently attracted attention owing to their unique features. There are numerous promising applications of ZnO nanoparticles in veterinary science due to their wound healing, antibacterial, antineoplastic and antigenic properties. Recently, many research studies and experimental analyses have improved the efficiency of zinc oxide (ZnO) materials by producing nano-structures where each nano-dimension is reduced to generate nanowires, thin films and other structures for plenty of applications including defense against intracellular pathogens and brain tumors. 10 One-dimensional structures include nanorods, 11–13 nanoneedles, 14 nanohelixes, nanosprings, nanorings, 1 nanoribbons, 15 nanotubes, 16–18 nanobelts, 19 nanowires 20–22 and nanocombs. 23 Nanoplates/nanosheets and nanopellets 24,25 are their two-dimensional forms while flowers, dandelions, snowflakes, coniferous urchin-like structures, etc. 26–29 count as the three-dimensional morphologies of ZnO nanoparticles. Nevertheless, the challenges in terms of the potential toxic effects of ZnO nanoparticles do require special attention.

2. Chemical methods for synthesis of zinc oxide nanoparticles

2.1 Mechanochemical process

Ao et al. 32 carried out a mechanochemical process of synthesizing ZnO NPs by exploiting the reaction between ZnCl 2 and Na 2 CO 3 and using NaCl as a diluent. 32 The pure nanocrystalline ZnO was obtained by removing the by-product NaCl and finally drying in a vacuum. TEM images showed moderately aggregated ZnO nanoparticles of size less than 100 nm which were prepared by a 6 h milling followed by a thermal treatment at 600 °C for 2 h. The effect of milling time and annealing was carefully investigated in the study. A decrease in nanocrystallite size from 25 nm to 21.5 nm was observed as the milling time increased from 2 to 6 h after which it attained steadiness. This phenomenon was chalked up to a critical effect prevailing in the course of milling. The crystal size, however, was found to increase with temperature with the rise being steep after 600 °C. The activation energies for nanocrystallite growth in different temperature ranges were calculated using the Scott equation. The activation energy was found to be 3.99 for growth in between 400 and 600 °C while it reached 20.75 kJ mol −1 beyond 600 °C. The higher growth rate at higher temperatures was thus attributed to extensive interfacial reactions driven by greater activation energy.

While the XRD analysis substantiated a perfect long-range order and a pure wurtzite structure of the synthesized ZnO powders regardless of the milling time, Raman spectroscopy revealed that lattice defects and impurities were introduced into ZnO powders at the middle-range scale depending on milling duration. Extended milling was found to reduce crystal defects but introduce impurities. The SEM images suggested that the milling duration of the reactant mixture positively regulated the morphology of the particles irrespective of the additional thermal treatment.

ZnO NPs were also prepared through a mechanochemical method by using ZnCl 2 , NaCl and Na 2 CO 3 as starting materials. 34 A solid phase reaction triggered by milling the starting powders led to the isolation of ZnCO 3 in the NaCl matrix. The ZnCO 3 was finally subjected to a thermal treatment at 400 °C which induced its decomposition to ZnO. The anatomization of TEM results indicated a mean particle size of 26.2 nm. The mean nanocrystallite size evaluated from the XRD peak width at 2 θ = 36° using the Scherrer equation was found to be 28.7 nm. Meanwhile, the surface area of the ZnO nanopowder evaluated from BET analysis was 47.3 m 2 g −1 corresponding to a spherical particle size of 27 nm.

Another study on the optical properties of ZnO NPs synthesized through mechanochemical means and using ZnCl 2 , NaCl and Na 2 CO 3 as raw materials was conducted by Moballegh et al. 35 The XRD and TEM results revealed that particle size increased with calcination temperature. The work proposed improved optical properties as a result of the decrease in particle size owing to the enhanced ratio of surface to volume in ZnO NPs. In another study 36 a mixture of starting powders (anhydrous ZnCl 2 , Na 2 CO 3 and NaCl) was milled at 250 rpm and then calcined at 450 °C for 0.5 h to yield ZnO NPs with a crystallite size of 28.5 nm as estimated from subsequent XRD analysis. The particle size that emerged from TEM and SEM analysis ranged in between 20 and 30 nm. The incongruent particle size estimated from BET analysis was ascribed to an agglomeration of nanoparticles in the course of drying.

The foremost shortcoming of the procedure exists in its fundamental difficulty encountered in the homogeneous grinding of the powder and controlled minimization of the particles to the required size. Note that the particle size reduces with increasing time and intensity of milling. However, if the powder is subjected to milling for longer periods of time, the chances of contamination increase. A highly shrunk size of nanoparticles is the prime advantage that can be extracted from the method apart from the benefit of a significantly low cost of generation coupled with diminished agglomeration of particles and pronouncedly homogeneous crystallite morphology and architecture. The mechanochemical process is particularly desirable for large-scale production of ZnO NPs.

2.2 Controlled precipitation

Kumar et al. 38 used zinc acetate (Zn(OAc) 2 ·2H 2 O) and NaOH as reagents, and the settled white powder was separated followed by washing with deionized water thrice and dried overnight under dust-free conditions at room temperature. XRD revealed the formation of hexagonal ZnO nanostructures. SEM and TEM analyses revealed the formation of crystalline ZnO flowers in which a bunch of ZnO nanorods assembled together to form a leaf-like structure followed by flower-shaped ZnO nanostructures. The ZnO nanoflowers were each formed by the combination of 8–10 leaf-like petals as shown. The length of each petal did not exceed 800 nm. The as-synthesized ZnO nanostructures showed good antimicrobial activity towards Gram-positive bacteria Staphylococcus aureus as well as Gram-negative bacteria Escherichia coli with a MIC/MBC of 25 mg L −1 . Zn(CH 3 COO) 2 ·2H 2 O and (NH 4 ) 2 CO 3 were employed as reagents by Hong et al. 39 in their method of synthesizing ZnO NPs. XRD and TEM tests revealed particle sizes of 40 and 30 nm. Heterogeneous azeotropic distillation thoroughly prevents agglomeration and reduces the size of ZnO NPs.

In the precipitation method of synthesizing nanopowders, it is more or less a ritual these days to use surfactants that would enable control over the growth of particles with the simultaneous prevention of coagulation and flocculation of particles thereby preventing an appreciable reduction in the final yield. The surfactants act as chelates encapsulating the metal ions in an aqueous medium. Wang et al. 41 used ZnCl 2 and NH 4 OH and a cationic surfactant, CTAB (cetyltrimethyl-ammonium bromide), for the generation of ZnO NPs. The formation of sharply crystalline ZnO NPs with a wurtzite structure and crystallite size of 40.4 nm was confirmed by XRD data, while TEM examination of the powder bore out the formation of spherical nanoparticles of size 50 nm.

2.3 Sol–gel method

Suwanboon et al. 43 using Zn(CH 3 COO) 2 ·2H 2 O, polyvinyl pyrrolidone (PVP) and NaOH prepared nano-structured ZnO crystallites via the sol–gel method. The XRD characterization revealed a wurtzite structure having an average crystallite size of about 45 nm. The role of PVP at its different concentrations on the morphology was checked. There occurred a shift from a platelet-like to a rod shape with an increase in PVP concentration. TEM images bore out the grain size of platelet-like ZnO to be 150 nm while the diameter of the rod-shaped ZnO was likewise determined to be 100 nm. In another sol–gel method-based synthesis by Benhebal et al. 44 zinc acetate dihydrate and oxalic acid were used to generate ZnO nanopowder with ethanol as a solvent which showed a hexagonal wurtzite structure. The crystallite size obtained from the Scherrer equation was found to be 20 nm. The SEM micrograph confirmed the formation of uniform, spherically shaped ZnO nanoparticles. BET analysis revealed a surface area of 10 m 2 g −1 . This was characteristic of a material with low porosity, or a crystallized material.

Sharma 45 obtained ZnO NPs with outstanding antibacterial properties using the sol–gel method. Zinc acetate, oxalic acid and water were employed as raw materials in this process. A white gel precipitate was first obtained. It was then thermally treated at 87 °C for 5 h, and then at 600 °C for 2 h. The ZnO NPs exhibited high crystallinity as borne out by XRD data. A diameter of 2 μm was obtained for the ZnO nano-aggregates from SEM analysis.

In a study conducted by Ristic et al. 46 nano-structured ZnO crystallites were obtained using the sol–gel route. From XRD examination and using the Scherrer formula, the average value of the basal diameter of the cylinder-shaped crystallites was found to be 25–30 nm, while the height of the crystallites was 35–45 nm. The sol–gel method presents a host of advantages in comparison with the previously mentioned methods. Prime amongst its merits are the low cost of the apparatus and raw materials, reproducibility and flexibility of generating nanoparticles. 47

2.4 Vapour transport method

In water vapour, ZnO nanoflowers were synthesized. The nanoflowers were constructed from tens of ZnO nanosheets with random orientations. In oxygen gas, ZnO hexagonal nanorods were obtained. The size of the nanorods was not uniform. It was argued that the size of the Au catalyst underneath might have influenced the size of the ZnO nanorods. Both the samples, however, exhibited a hexagonal wurtzite structure. Though the samples showed different morphologies and crystal structures, surprisingly, they had almost the same optical properties. The PL spectra revealed only one UV peak close to 389 nm wavelength for both samples, indicating the high quality of the synthesized ZnO samples.

Novel one-dimensional single-crystalline ZnO nanorod and nanoneedle arrays on a Cu catalyst layer-coated glass substrate were investigated by Alsultany et al. 50 via a simple physical vapour deposition method by thermal evaporation of Zn powder in the presence of O 2 gas. The ZnO nanorods and nanoneedles were synthesized along the c -axis growth direction of the hexagonal crystal structure. The diameter and growth rate of the high-quality and well oriented one-dimensional ZnO nanostructures were achieved as a function of varying growth temperature and growth time. At 450 °C, ZnO nanorods were uniformly distributed at a high density on the entire substrate surface and quasi-aligned, and small average diameters were obtained. The diameters and lengths of the obtained nanorods were in the range of 19–27 nm and 2.8 μm, respectively. When the temperature was increased to 550 °C, ZnO nanorods grew perpendicular to the substrate, uniformly throughout their length, and with more consistent shape and dimensions, with approximately 85 nm width and 3.8 μm length. The morphological change and distribution occurred at a growth temperature of 650 °C, and ZnO nanorods with a hexagonal shape at the tips of rods of hexagonal hierarchical structures were formed. These rods possessed a typical hierarchical structure with lengths and diameters of approximately 190–350 nm and 3.9 μm, respectively, whereas short nanorods with a diameter of 95 nm and length of 900 nm were observed on the tip of each rod of hexagonal hierarchical structures. As Cu metal catalysts were used in the study, the growth mechanism of 1D ZnO nanostructures presented therein followed the VLS method. This method could be divided into three stages, as follows: first, the Zn vapor and catalytic Cu formed liquid alloy droplets during the heating process at a certain temperature, representing the initial stage of the nucleation process. Second, crystal nucleation occurred upon gaseous species adsorption until supersaturation was reached, and the formed sites served as nucleation sites on the substrate. Finally, the axial growth of the nanorods began from these sites. Based on this study of the mechanism in the presence of Cu metal catalysts at different growth temperatures and according to the nucleation theory of the VLS growth mechanism, the Cu catalyst nanoclusters formed because of capillarity, which caused beading of the Cu layer at high growth temperature. Consequently, the Cu–Zn alloy process reached a certain solubility depending on the temperature; then, the Zn vapor began to precipitate out at the interface between the surface and droplet. That in turn determined the diameter and size of the nanostructures depending on the size of the liquid alloy droplets. Notably, large-scale ZnO nanorods with a lower diameter were formed at a low growth temperature of 450 °C. The Zn metal powder (melting point of 419 °C) vapor pressure at 450 °C was sufficiently high to investigate the growth of ZnO nanorods on the glass substrate via the VLS method, and the decrease in Zn vapor as a result of the decrease in the growth temperature led to a low lateral growth rate compared with the axial growth rate of the 1D nanostructure. In contrast, the higher growth temperature could also lead to the formation of hierarchical nanostructures. In addition, at high growth temperature along with the consumption of the Zn vapor during growth, the diameter of the nanorods markedly decreased. This condition consequently caused the production of rods with a typical hierarchical structure. At a growth time of 30 min, ZnO nanorods were obtained with a diameter of 19–27 nm and a length of 2.8 μm. When the growth time increased to 45 min, nanoneedles were obtained. The needles exhibited mean diameters of 65–190 nm and length of 3.2 μm. On the other hand, nanoneedles grown at 60 min were approximately 80–250 nm in diameter and 3.8 μm in length.

Diep and Armani 51 designed a flexible light-emitting nanocomposite based on ZnO nanotetrapods (NTPs) which they prepared using a vapour transport technique. The CVT synthesis of the ZnO NTPs was self-catalyzed. In the TEM images, the lattice fringes were clearly visible, indicating the single-crystalline nature of the nanostructures. The lattice spacing was found to be 2.6 Å, indicating growth in the [0001] direction. X-ray diffraction (XRD) and energy-dispersive X-ray spectroscopy (EDX) analysis were also performed to confirm the crystal structure and elemental composition of the NTPs. Based on an analysis of the TEM and SEM images, the ZnO NTP arm lengths ranged from 0.5 μm to 3.5 μm and the diameters varied from 120 nm to 350 nm.

Luo et al. 52 also constructed ZnO tetrapods as potential electrode materials for low-cost and effective electrochemical supercapacitors using an oxidative-metal-vapor-transport method. The SEM images of the ZnO tetrapods collected at different temperatures showed that the products obtained were pure and uniform, and the tetrapods consist of four arms branching from one center, and the angles between the arms were nearly the same, analogous to the spatial structure of the methane molecule. As for the size variation with collected temperatures, it transpired that smaller size tetrapods were obtained with lower evaporation temperature. This demonstrated the power of the technique for controlling the size of the tetrapods. ZnO tetrapods with arms as thin as about 170 nm and shorter than 4000 nm were revealed by SEM analysis. The XRD pattern of the ZnO tetrapods showed that all the diffraction peaks could be indexed to a wurtzite 5 structure with lattice constants of a = 0.324 nm and c = 0.519 nm. The TEM and high resolution TEM (HRTEM) images of the ZnO tetrapods revealed that the arm diameter and length of the tetrapods are, on average, about 22 nm and 90 nm, respectively. The HRTEM image of a single arm revealed clear fringes perpendicular to the arm axis and these fringes were spaced by about 0.25 nm consistent with the interplanar spacing of (0002) suggesting that the nanowire growth direction was along [0001].

2.5 Hydrothermal method

Aneesh et al. 54 carried out an experiment in which they used Zn(CH 3 COO) 2 ·2H 2 O, NaOH and methanol as reagents. The ZnO NPs thus formed had a hexagonal wurtzite structure. XRD analysis demonstrated an enhancement in average grain size with rising temperature and concentration of the substrates. The average grain size of ZnO NPs prepared from 0.3 M NaOH employing a growth time of 6 h was found to increase from 7 to 16 nm with temperature rise from 100 to 200 °C. The average grain size of ZnO synthesized at 200 °C for 12 h revealed an increase from 12 to 24 nm with elevation in concentration of NaOH from 0.2 M to 0.5 M.

This process has many advantages over other methods. Organic solvents do not find use in this process. This coupled with the omission of supplementary processes like grinding and calcination within the ambit of the method endows it with the much sought after eco-friendly character. Low operating temperatures, the diversified morphologies and sizes of the resulting nano-crystals depending on the composition of the starting mixture and the process temperature and pressure, the greatly pronounced crystallinity of the nanoparticles and their high purity are factors that surely make the process more advantageous than others. 54,55

2.6 Solvothermal method

Chen et al. 57 also used a solvothermal route to generate ZnO NPs. They eventually prepared nano-structured ZnO crystals that were devoid of hydroxyl groups. They carried out a reaction of zinc powder with trimethylamine N -oxide (Me 3 N→O) and 4-picoline N -oxide (4-pic→NO). The medium for the reaction was a mixture of organic solvents (toluene, ethylenediamine (EDA) and N , N , N ′, N ′-tetramethylenediamine (TMEDA)) contained in an autoclave which was kept at 180 °C. It was observed that the size and morphology of the ZnO nanoparticles/nanowires were greatly influenced by the oxidants used and the ligating capacities of the solvents. The ramifications of the presence of water in the system were additionally investigated. It emerged that the presence of traces of water catalyzed the zinc/4-picN→O reaction and exerted an effect on the size of the nano-structured ZnO crystallites thus obtained. Depending on the reaction conditions, the ZnO nanostructures had diameters ranging in between 24 and 185 nm. The solvothermal synthesis method has many advantages. Foremost among them is the fact that reactions can be carried out under determined conditions. As a result, nano-structured ZnO with a range of architectures can be generated by exercising due control over the reaction conditions.

2.7 Method using an emulsion or microemulsion environment

SEM and XRD analysis showed that the particle size and phase location were both dependent upon the conditions (ratio of two-phase components, substrates and temperature) employed for the accomplishment of the process. Depending on the process conditions, ZnO NPs with different particle morphologies were obtained. The morphologies that formed during the process included spherical agglomerates, needle shapes, near-hexagonal shapes, near-spherical shapes and irregular agglomerates. These NPs further had a wide range of diameters. Some had diameters ranging in between 2 and 10 μm, while the diameters of others ranged from 90 to 600 nm, some others had diameters in between 100 and 230 nm and yet others were characterized by diameters hovering around 150 nm.

Kołodziejczak-Radzimska et al. 59 used zinc acetate and KOH or NaOH in an emulsion system. For the generation of an emulsion, cyclohexane was utilized. Cyclohexane was held to have furnished a ready organic phase, and also essayed the role of a surfactant that wasn't ionic. In this method for emulsion formation cyclohexane was used as an organic phase, and nonylphenyl polyoxyethylene glycol ethers NP3 and NP6 were used as a mixture of emulsifiers. By tailoring the ZnO precipitation process by way of altering the precipitating agent, substrate ingredients and the tempo of substrate dosing, an amazing variety of ZnO nanostructures were designed. Four samples were obtained, labelled Z1, Z2, Z3, and Z4, composed of particles of different shapes. Morphologies such as solids (Z1), ellipsoids (Z2), rods (Z3) and flakes (Z4) with modal diameters of ∼396 nm, ∼396 nm, ∼1110 nm and ∼615 nm were obtained. They were further characterized by their considerable surface areas. Values of 8 m 2 g −1 , 10.6 m 2 g −1 , 12 m 2 g −1 and 23 m 2 g −1 could be respectively assigned to samples Z1, Z2, Z3, and Z4.

If a surfactant possessing balanced hydrophilic and lipophilic properties is used in the right proportion, a different oil and water system will be produced. The system remains an emulsion, but exhibits some characteristics that are different from emulsions. These new systems are “microemulsions”. The drop size in a microemulsion is significantly smaller than in an emulsion, and lies in the range 0.0015–0.15 μm. 60,61 In contrast to emulsions, microemulsions form spontaneously under appropriate conditions. This synthesis method does not require any complex preparation procedure, sophisticated equipment or rigorous experimental conditions, but still provides possibilities in controlling the size and morphology of the ZnO powders in a size scale approaching nanometers. Even though the product yield is low, the narrow size distribution due to well-dispersed cage-like small reactors (5–100 nm) formed under uniform nucleation conditions is the superior aspect of the ZnO nanoparticles obtained by microemulsion routes. Such low-dimensional uniform ZnO nanostructures offering size and morphology dependent tunable electrical and optical properties are of particular technological interest for applications such as quantum dots, UV-emission optoelectronic and lasing devices, and transparent conducting thin films.

Yildirim and Durucan 63 also synthesized ZnO NPs through the use of microemulsions. They made an endeavour to reshape the microemulsion modus operandi with an eye to generate monodisperse ZnO nanostructures. They subjected the zinc complex precipitate obtained in the course of the microemulsion method to thermal decomposition. Subsequent calcination was adopted. The use of glycerol as the internal phase of a reverse microemulsion imparted the intended modification. The synthesized ZnO NPs had spherical shapes. They were monodisperse and their diameter measured in between 15 and 24 nm.

All the procedures involving chemical synthesis of ZnO NPs generate a few toxic chemicals and their adsorption on the surface increases the likelihood of harmful effects being wielded in medical applications. Further, these approaches include reactions requiring high temperature and intense pressure for their commencement while some reactions require operations in an inert atmosphere or under inert conditions. Toxic materials such as metallic precursors, toxic templates and capping agents and even H 2 S find application in quite a few chemical routes. 64 Very often toxic substances are employed for the generation of nano-structured particles and for their stabilization as well. This in turn produces secondary products and residues that are detrimental to the ecosystem. 65,66

3. Green methods for the synthesis of ZnO nanoparticles

An extract prepared from Ajwain ( Carom-Trachyspermum ammi ) seeds has also been used to synthesize ZnO NPs. 70 The work boasts of its operation under ambient temperature conditions. The ZnO NPs were found to have a wurtzite structure. The synthesized ZnO nanostructures were morphologically characterized by FE-SEM images. The ZnO nanostructure showed uniform hexagonal plates, as well as irregular and highly aggregated nanoparticles with a rough surface. The average diameter of the nano-sized ZnO clusters has been observed to be ∼41 nm. XRD results showed an increase in interplanar spacing with an increase in the extract volume from 0.2474 nm to 0.2765 nm with a simultaneous decrease in crystallite size from 39.51 nm to 28.112 nm. The band gap also fell from 3.592 eV to 3.383 eV as the amount of extract increased. Phytoconstituents in the extract thus evidently played a key role of reductants and furthermore acted as capping agents in the generation and stabilization of ZnO NPs.

Jamdagni et al. 72 used an aqueous flower extract of Nyctanthes arbortristis for making ZnO NPs. The starting materials consisted of zinc acetate dihydrate and sodium hydroxide. XRD results showed an average crystallite size of 16.58 nm while TEM analysis revealed that the individual particle size ranged within 12–32 nm and the nanoparticles were obtained in the form of aggregates. In a very recent study, 73 Ulva lactuca seaweed extract was used to prepare ZnO nanoparticles. XRD analysis revealed strong characteristic peaks of ZnO suggesting high crystallinity of the synthesized material. Further, the average crystallite size thus calculated was found to range in between 5 and 15 nm. TEM micrographs revealed an agglomeration of asymmetrically shaped NPs bearing an average crystallite size of 15 nm.

Muraya koenigii seed extract was also recently reported to have been used as a stabilizer as well as a reductant in the preparation of ZnO NPs. 74 Sharp diffraction peaks in XRD results indicated remarkable crystallinity of the NPs whose average crystallite size was calculated to be 70–100 nm. Both SEM and TEM micrographs revealed nanoparticles with an average size of about 100 nm and bearing a wide range of morphologies – spherical, triangular, radial, hexagonal, rod-like and rectangle-shaped.

One recent experiment used Calotropis procera leaf extract and Zn(NO 3 ) 2 ·6H 2 O to synthesize ZnO NPs. 75 An XRD test confirmed a hexagonal wurtzite structure of the nanoparticles with marked crystallinity. The average crystallite size was calculated using the Scherrer equation and found to be 24 nm. Diffuse Reflectance Spectroscopy (DRS) revealed a band gap of 3.1 eV for the synthesized nanoparticles. In the FT-IR analysis of the synthesized ZnO NPs, a peak attributed to the metal–oxygen bond of ZnO appeared in between 500 and 700 cm −1 . Further, a conspicuous shift and broadening of peaks corresponding to functional groups like hydroxyl, aldehyde, amine, ketone, and carboxylic acid suggests their participation in the stabilization of ZnO by the extract. Surface attachment of groups like aldehyde, amine, phenol and terpenoid enhances stabilization additionally allowing the extract to function as a bio-template thereby preventing aggregation of ZnO NPs. TEM images revealed an average particle size of 15–25 nm, while SAED and HR-TEM further confirmed the high crystallinity of the material prepared.

The effects of Artocarpus heterophyllus leaf extract and varying temperatures on the morphology and properties of the ZnO NPs thus prepared were studied by Vidya C. et al. 76 XRD results show an increase in crystallinity and average crystallite size with temperature, the diffraction peaks being increasingly sharper and narrower with temperature. The particles were all spherical and a grain size of 50 nm was obtained from SEM images. SEM analysis also shows similar trends of size and morphology upon temperature variation. TEM analysis revealed a particle size of ∼10–15 nm at 400 °C, ∼15–25 nm at 600 °C and ∼25–30 nm at 800 °C. This further corroborated the results of XRD and SEM tests. Diffuse Reflectance Spectroscopy (DRS) showed a decrease in the calculated band gaps with increasing calcination temperatures.

Archana et al. 77 used Moringa oleifera natural extract and Zn(NO 3 ) 2 ·6H 2 O for the preparation of ZnO NPs. They took different volumes of the extract, viz. 2, 6, 10 and 14 mL, to prepare ZnO NPs which were accordingly labeled ZnO-2, ZnO-6, ZnO-10 and ZnO-14. The PXRD results of all the samples showed great crystallinity. They had a hexagonal wurtzite structure. And the average crystallite size was found to be 21.6 nm. Field Emission Scanning Electron Microscopy (FE-SEM) analysis showed highly crystalline ZnO-10 and ZnO-14 having a spherical shape and average crystallite size of 20–150 nm. HR-TEM micrographs revealed d -spacing of 0.28 and 0.19 nm for the (001) and (101) planes of wurtzite ZnO. The band gaps calculated using the results from Diffuse Reflectance Spectroscopy (DRS) had values of 2.92 eV for ZnO-2, 3.05 eV for ZnO-6, 3.12 eV for ZnO-10 and 3.10 eV for ZnO-14. The increase in band gap with the amount of fuel was attributed to quantum size effects.

In their research work, Rajeswari Rathnasamy et al. 78 used papaya leaf extract for the synthesis of ZnO NPs. Both FESEM and TEM data revealed an average size of ∼50 nm for the individual nanoparticles. The extract of Nephelium lappaceum L. (rambutan) peels (a natural ligation agent) was put into use for the preparation of ZnO NPs in another investigation. 79 The bio-mediated ZnO NPs were found to be spherical in shape. They were characterized by diameters between 20 and 50 nm. Some of the particles were found in agglomerated form. After a day, multi-dimensional chain-like structures formed. In these chains spherical nanoparticles were found intertwined to each other.

An investigation conducted by Matinise et al. 80 used Moringa oleifera extract as a remarkably operative chelating agent to prepare ZnO nanoparticles. The ZnO NPs eventually obtained were characterized by a particle size in between 12.27 and 30.51 nm. The sample obtained just after drying at 100 °C consisted of agglomerates of spherical particles while that obtained after annealing at 500 °C also had nanorods in addition to the clusters of spherical nanostructures.

The biocomponents of leaves of Catharanthus roseus have also been utilized to prepare ZnO NPs with zinc acetate and sodium hydroxide as reagents. 81 SEM micrographs revealed that in addition to the individual ZnO-NPs, aggregates were also formed and they were spherical with diameter ranging from 23 to 57 nm. Sharp and clear XRD peaks confirmed high purity and excellent crystallinity. Shah et al. 82 generated ZnO NPs using the aqueous extract of green tea ( Camellia sinensis ) leaves. The size of the particles was determined using a particle size analyzer. The average diameter of the particles was found to be 853 nm. These nano-sized ZnO particles demonstrated remarkable antimicrobial properties against Gram-positive and Gram-negative bacteria as well as against a fungal strain.

In another experiment, 50 mL of aqueous Citrus aurantifolia extract was boiled to 60–80 °C. 83 It was followed by the addition of a specific amount (5 g) of Zn(NO 3 ) 2 to the solution as its temperature rose to 60 °C. The synthesized nanoparticles were characterized by moderate stability. They had near-spherical shapes with the most probable particle size in the range of 9–10 nm. The extract of Oryza sativa rice 84 was also used to generate ZnO NPs. The extract has been considered a renewable bio-resource. Its abundance adds to its list of merits. The extract has also been cited as a source of bio-template that typically assists the generation of a variety of multifunctional nano-structured materials. ZnO NPs were prepared using the hydrothermal method. The method involved the use of zinc acetate, sodium hydroxide, and uncooked rice flour at several ratios at 120 °C for 18 h. The rice bio-template was found to exert considerable influences upon the size and morphology of ZnO NPs. Fig. 2 shows field emission scanning electron microscopy (FESEM) images of the samples synthesized at different concentrations of uncooked rice (UR). To investigate the effects of raw rice on the resulting ZnO morphology, FESEM was conducted on ZnO synthesized without UR ( Fig. 2a and b ). As seen in Fig. 2c and d , the ZnO structures were mostly flake-like structures assembling together. They were much more ordered in contrast to the one synthesized without UR (as a control) ( Fig. 2a and b ). The diameter of ZnO flakes dramatically decreased after adding 0.25 g UR. This was proposed to have occurred due to the inhibition of lateral growth of ZnO crystals. It was further proposed that the accessibility of the zinc ions to the ZnO crystal seeds was controlled by a bio-template. However, the size of particles seemed to increase when the synthesis was done using 0.25 g UR. Different morphologies of the as-synthesized ZnO were observed with increasing the amount of uncooked rice to 0.5 g. Particles with a very small flower-like shape could be observed ( Fig. 2e and f ). A lower magnification FESEM image indicated that the mentioned structure showed denticulated petals aggregated and form larger flowers of particles. Notably the size of the ZnO particles had been obviously decreased for the sample prepared using 0.5 g UR. In addition, the tooth-like flakes were more dominant for the ZnO sample prepared using 0.5 g UR compared to the one synthesized using 0.25 g UR. Fig. 1g and h indicate the FESEM images of the ZnO sample synthesized using 1 g UR. A very unique star-like structure could be clearly observed at low to high magnification. The star-like structure contained small flakes with denticulated edges which attach to other similar flakes in the center. A closer look showed that the lateral flake acted as a substrate for other flakes to grow on the surface and form a star-like structure. It was therefore argued that the branched pattern for soft templates of starch revealed that the semicrystalline granules of starch were made from concentric rings in which the amylose and amylopectin basic components were aligned perpendicularly to the growth rings and to the granule surface. Fig. 2g and h show that the size of the star-like ZnO particles decreased in comparison with the previous lower amount of uncooked rice. In the case of ZnO crystals synthesized at 2 g UR, increasing the amount of bio-template resulted in different morphologies of ZnO particles being produced. It formed lots of agglomerated toothed-edge flakes which became a secondary unit for larger particles. The star-like shape of the particles could be perceived in some areas but aggregation seemed to be dominant and prevented clearer observation of the particles as they really are. Fig. 2k and l show the FESEM images of the as-synthesized ZnO particles synthesized using 4 g UR. The ZnO morphology changed to flower-like structures, mostly rose-like shapes. A detailed view of the flower-like particles revealed that their flakes had the largest diameter compared to other samples. In the case of ZnO synthesized using 8 g UR, a new morphology, different from other and control samples, was observed. The ZnO crystals appear mostly as rods with around 100 nm size. Moreover, agglomerated without any specific shape, particles coexisted with nanorods in the structure of ZnO synthesized using 8 g UR. Fig. 3 shows the particle size distribution of the ZnO samples synthesized using 0.25, 0.5, 1, 2, 4, and 8 g UR. The particle size distribution of ZnO synthesized without rice is also given for comparison. As shown in Fig. 3 , the range of particle size for ZnO synthesized without UR lies between 200 and 800 nm. When 0.25 g UR was used in the synthesis, the size of particles increased dramatically to 800–2000 nm. Notably the size of ZnO synthesized using 0.5 g UR considerably decreased to the 200–1000 nm range. The decreasing trend continued for the sample synthesized using 1 g UR and with a size range of 250–700 nm. Although this distribution was quite similar to that of ZnO synthesized without a bio-template, it was slightly narrower. On the basis of the particle size distribution for the samples synthesized using 2 and 4 g UR, it could be clearly observed that the size of particles decreased to 200–700 nm and 150–700 nm, respectively. In the case of the ZnO sample synthesized using 8 g UR, the size of particles was within the nano regime, between 40 and 100 nm. As mentioned in the growth mechanism suggested by the study, adding a bio-template, which presumably acts as a flocculant, forces aggregation. Therefore, the surface-active sites of the template might influence the size and state of aggregation during the particle growth process and ultimately the resulting ZnO particle size distribution. Another procedure used the aqueous leaf extract of Passiflora caerulea. L. (Passifloraceae). 85 The SEM analysis revealed that the ZnO NPs had diameters ranging in between 30 and 50 nm.

Sucrose was used in a study as the capping agent to synthesize a ZnO/C nanocomposite adapting the sol–gel method. 86 The presence of carbon in the prepared ZnO/C was confirmed through EDAX. SEM images of the ZnO/C samples indicate a wide distribution of particles ranging from 10 to 100 nm and exhibit only an irregular granular feature. This kind of surface morphology was argued to be more suitable for supercapacitor electrode materials. Electrochemical investigations of the ZnO/C electrode were carried out using cyclic voltammetry, galvanostatic charge–discharge, and electrochemical impedance spectroscopy. The ZnO/C electrode exhibits a maximum specific capacitance of 820 F g −1 at a constant specific current of 1 A g −1 . The symmetric aqueous supercapacitor device exhibits a specific cell capacitance of 92 F g −1 at a specific current of 2.5 A g −1 . The aqueous symmetric supercapacitor device achieved an energy density of 32.61 W h kg −1 and a power density of approximately 1 kW kg −1 at a discharge current of 1.0 A g −1 . It has been found that the cells have an excellent electrochemical reversibility (92% after 400 continuous cycles) and capacitive characteristics in 1 M Na 2 SO 4 electrolyte.

Zinc oxide (ZnO) nanoparticles were successfully synthesized using a whey-assisted sol–gel method. 87 X-ray diffraction (XRD) and Raman spectroscopy analysis revealed a wurtzite crystalline structure for ZnO nanoparticles with no impurities present. Transmission electron microscopy (TEM), XRD observations, and UV-vis absorption spectroscopy results showed that with an increase in calcination temperature from 400 to 1000 °C, the size of the spherical nanoparticles increased from 18.3 to 88.6 nm, while their optical band gap energy decreased to ∼3.25 eV. The whey-assisted sol–gel method proved to be highly efficient for the synthesis of crystalline ZnO nanoparticles whose applications are of great interest in materials science technology. Eryngium foetidum L. leaf extract was also used for the nontoxic, cost-effective biosynthesis of ZnO nanoparticles (NPs) following the hydrothermal route. 88 The biosynthesized ZnO NPs served as an excellent antibacterial agent against pathogenic bacteria like Escherichia coli , Pseudomonas aeruginosa , Staphylococcus aureus susp. aureus and Streptococcus pneumoniae . The maximum zone of inhibition in ZnO NPs is 32.23 ± 0.62 and 28.77 ± 1.30 mm for P. aeruginosa and E. coli , respectively.

Another report presented an efficient, environmentally friendly, and simple approach for the green synthesis of ZnO nanoparticles (ZnO NPs) using orange fruit peel extract. 89 The approach aimed to both minimize the use of toxic chemicals in nanoparticle fabrication and enhance the antibacterial activity and biomedical applications of ZnO nanoparticles. The sample obtained without annealing exhibited relatively small spherical particles (10–20 nm) which were coagulated in large clusters on a matrix of residual organic material from the reducing agents. In the samples annealed at 400 °C and 700 °C, the particle sizes were randomly distributed and ranged from 35 to 60 nm and 70 to 100 nm, respectively. For an annealing temperature of 900 °C, the particle size increased intensively in the range of 200–230 nm. It was thus found that the morphology and size of the ZnO NPs depended on the annealing temperature. Specifically, with increasing annealing temperature, the particle size tended to increase and shape larger particles due to crystal growth. For pH values of 4.0 and 6.0, the particles were sphere-like in shape, and were distorted with distinct grain boundaries and low coagulation. At pH = 6, the particle size was in the 10–20 nm range and exhibited relative separation. Meanwhile, for a pH of 8.0, the particles had a variable shape and were coagulated in large clusters around 400 nm in size with indistinct grain boundaries. For a pH of 10.0, the particles were coagulated into large blocks with lengths of ∼370 nm and widths of ∼160 nm. The ZnO NPs exhibited strong antibacterial activity toward Escherichia coli ( E. coli ) and Staphylococcus aureus ( S. aureus ) without UV illumination at an NP concentration of 0.025 mg mL −1 after 8 h of incubation. In particular, the bactericidal activity towards S. aureus varied extensively with the synthesis parameters. This study presents an efficient green synthesis route for ZnO NPs with a wide range of potential applications, especially in the biomedical field.

4. Modification of zinc oxide nanoparticles

Cao et al. 90 used silica and trimethyl siloxane (TMS) for modifying ZnO in order to achieve a two-fold benefit: enhancing the compatibility of ZnO and cutting down on its agglomeration in the organic phase. A chemical precipitation method using zinc sulfate heptahydrate (ZnSO 4 ·7H 2 O), ammonium solution (NH 4 OH) and ammonium bicarbonate (NH 4 HCO 3 ) was adopted to first obtain the precursor, zinc carbonate hydroxide (ZCH). The surface of the ZCH was then successively modified by an in situ method using TEOS and hexamethyldisilazane (HMDS) in water. The functionalized ZHC was subjected to calcination, to yield extremely fine nanoparticles of ZnO. Reduced agglomeration was thereby effected through such functionalization of the surfaces of ZnO NPs although a lowered photocatalytic activity of the oxide was observed. Nevertheless, a marked increase in the compatibility of ZnO with the organic matrix lent credence to the method. Further, the greater shielding capacity of UV radiation renders the synthesized nanomaterial an excellent candidate for use in cosmetics. Below is a schematic representation ( Fig. 4 ) of the synthesis of surface-modified ZnO ultrafine particles using an in situ modification method.

The FTIR spectra for the SiO 2 -modified ZnO revealed interphase bonds between ZnO and SiO 2 . A thin film coating of SiO 2 on the ZnO surface resulted in enhanced dispersion and reduced agglomeration of nanoparticles, a fact fairly well corroborated by HR-TEM data. The photocatalytic activity of SiO 2 -modified ZnO however suffered a setback in comparison with that demonstrated by uncoated ZnO. The work further demonstrated that the thorough reduction of the crystallinity of ZnO achieved through heterogeneous azeotropic distillation of the zinc oxide precursor not only precludes aggregation but also brings about a decline in the average particle size.

Yuan et al. 93 modified ZnO using Al 2 O 3 . A basic carbonate of zinc was obtained from the reaction between zinc sulfate and ammonium bicarbonate followed by precipitating aluminum hydroxide over it. The resulting compound-precipitate was then calcined at 400–600 °C to obtain ZnO NPs coated with Al 2 O 3 . It was discovered from TEM analysis that as the Al 2 O 3 -coating content rose from 3 to 5%, agglomeration decreased significantly and correspondingly the particle size decreased from an average value of 100 nm to 30–80 nm. The coating thus designed was 5 nm thick and was highly uniform. The coating-core interphase possibly had the structure of ZnAl 2 O 4 . Zeta potential data clearly confirm modifications on the ZnO surface by Al 2 O 3 deposition. The change in pH at the isoelectric point for ZnO NPs upon coating with Al 2 O 3 from around 10 to a value of 6 might have assisted a greater degree of dispersion of ZnO NPs.

In a study by Hu et al. , 94 nano-sized ZnO rods doped with transition metals such as Mn, Ni, Cu, and Co were designed by a plasma enhanced chemical vapor deposition method. The ZnO thus modified had a greater amount of crystal defects within its structure. This led to its greater sensitivity towards formaldehyde. When the 1.0 mol% Mn doped ZnO nanorods were activated by 10 mol% CdO, a maximum sensing of ∼25 ppm was obtained and the corresponding response and recovery time were found to be appreciably short.

Wysokowski et al. 95 developed a β-chitin/ZnO nanocomposite material. The β-chitin used in the synthesis was derived from Sepia officinalis , a cephalopod mollusk. This nanocomposite was found to exhibit remarkable anti-bacterial activity and was touted as an excellent ingredient for the making of wound-dressing materials.

Ong et al. 96 in their work synthesized a heterogeneous photocatalytic material by loading ZnO on solvent exfoliated graphene sheets. For anchoring ZnO onto the graphene sheet, they used poly(vinyl pyrrolidone) as an inter-linker which was also found to enhance the functionalization of the acid treated graphene sheets. The thermal stability of the decorated ZnO was found to be higher than that of the undecorated oxide. The modified ZnO proved to be an outstanding photocatalyst being able to cause 97% degradation of Reactive Black 5 under visible light. This improvement was attributed to a host of favourable parameters achieved through the modification, namely, an enhancement of light absorption intensity, widening of the light absorption range, suppression of charge carrier recombination, improvement of surface active sites and rise in the chemical stability of the designed photocatalyst.

Tang et al. 97 demonstrated a way to tackle the agglomeration tendency of ZnO NPs. They prepared ZnO/polystyrene nanocomposites via a mini-emulsion polymerization method. For this, a silane coupling agent, namely γ-glycidoxypropyl trimethoxysilane (KH-560, AR), was first allowed to cling to ZnO NPs via reaction between its Si–OCH 3 groups and the hydroxyl groups on the surface of the nanoparticles followed by anchoring of 4,4′-azobis(4-cyanovaleric acid) (ACVA) onto their surface through reaction of its carboxyl groups with the terminal epoxy groups of the aforementioned coupling agent. Subsequently, polymerization of the styrene monomer was initiated using the azo group of ACVA for designing the final nanocomposites. The monomer droplet of the mini-emulsion polymerization system thus obtained contained well dispersed ZnO/polystyrene nanocomposites with a high grafting efficiency of 85% as calculated from TGA. It was evident from scanning electron microscopy (SEM) that while pure ZnO NPs suffered considerable agglomeration in poly(vinyl chloride) (PVC) film, the ZnO/polystyrene nanocomposite particles underwent homogeneous dispersion in the PVC matrix. The scheme depicted in Fig. 5 explains the mechanism of the mini-emulsion polymerization method to construct ZnO/polystyrene nanocomposites adopted by Tang and his research group. From SEM micrographs ( Fig. 5 ), it was observed that functionalized ZnO (f-ZnO) nanoparticles had been well dispersed in the polymer matrix because the f-ZnO nanofiller had outstanding adhesion and strong interfacial bonding to PEA. As was observed, f-ZnO nanoparticles were homogeneously dispersed in the polymer matrix and their sizes were estimated to be between 20 and 50 nm.

Cyclodextrins (CDs) make up a class of cyclic torus-shaped oligosaccharides. CD has a hydrophilic external surface and a hydrophobic internal cavity. CDs have been extensively used as eco-friendly coupling agents. 98,99 Among the derivatives of CDs, monochlorotriazinyl-β-cyclodextrin (MCT-β-CD) with a monochlorotriazinyl group as a reactive anchor was found to possess the ability to form covalent bonds with substituents of the nucleophilic type, viz. , –OH or –NH 2 groups. 100–103 Therefore, MCT-β-CD provides an interesting way of surface modification for inorganic nanomaterials. Abdolmaleki et al. 104 accomplished surface modification of ZnO NPs by covalently grafting MCT-β-CD onto the surfaces of ZnO NPs through a facile and single-step procedure. In the next step, f-ZnO nanoparticles were employed for construction of a new series of poly(ester-amide)/ZnO bionanocomposites (PEA/ZnO BNCs) whose TEM image is shown in Fig. 6 . MCT-β-CD has monochloro-triazinyl groups that react with –OH groups on the surfaces of ZnO NPs through nucleophilic reaction ( Fig. 7 ). After the incorporation of MCT-β-CD on the surfaces of ZnO NPs, polymer/ZnO bionanocomposites (BNCs) were designed using a biodegradable amino acid containing poly(ester-amide) (PEA). ZnO NPs with β-CD functional groups incorporated on their surfaces exhibited a near-complete suppression of their tendencies towards agglomeration while simultaneously displaying enhanced compatibility with the polymer matrix. Scores of functional groups on the surfaces of ZnO NPs enable possible interactions with PEA chains that lead to excellent dispersion and compatibility with the polymer matrix. FE-SEM and TEM results bore out a reduction of agglomeration that can be safely attributed to the steric hindrance induced by the organic chains of MCT-β-CD between the inorganic nanoparticles. The dispersibility, surface morphology and particle dimensions of functionalized ZnO (f-ZnO) with β-CD are shown in Fig. 8 .

5. Potential applications

5.1 Concrete and rubber industries

In their attempt to enhance the interactions between the nano-sized ZnO particles and the polymer, Yuan et al. 110 by incorporating vinyl silane groups on the surfaces of ZnO NPs using vinyl triethoxysilane through a procedure premised on the hydrosilylation reaction during curing carried out their surface modification. The vinyl silane groups on the ZnO surface enabled improved cross-linking with the rubber matrix. In order to solve this problem, surface modification techniques are applied to improve the interaction between the nanoparticles prepared by the sol–gel method and the polymer. In comparison with the nanocomposites of silicone rubber with ZnO, the nanocomposites of silicone rubber with vinyl triethoxysilane modified ZnO possessing extensive cross-linking and a higher degree of dispersion with the rubber matrix exhibited superior mechanical properties and enhanced thermal conductivity.

ZnO NPs have been widely used as an efficient material for the enrichment of cross-linking in elastic polymers. 111,112 The cured polymer produced through incorporation of ZnO NPs exhibited high ultimate tensile strength, tear strength, toughness and hysteresis. The slippage of polymer chains on the surfaces of ionic clusters and the renewal of ionic bonds when the sample gets externally deformed give rise to enhanced capacity of the ionic elastic polymer for stress relaxation which in turn results in its upgraded mechanical properties. Furthermore, the thermoplastic properties of such polymers enable their processing in a fused state in a manner akin to a thermoplastic polymer. 113 Nevertheless, carboxylic elastic polymers with ZnO as a cross-linker suffer from a few drawbacks prominent among which are their tendency to get scorched, feeble flex properties and high value of compression set. The tendency to get scorched is gotten rid of by the incorporation of either zinc peroxide (ZnO 2 ) or ZnO 2 /ZnO cross-linkers. ZnO 2 serves to not only create ionic cross-links but also generate covalent cross-links as a result of peroxide action. However, prolonged curing is needed to obtain elastomers with an ultimate strength and cross-link density comparable to that of ZnO-cross-linked elastomers. The three vital processes that amount to the curing of XNBR by ZnO 2 /ZnO cross-linkers are rapid creation of ionic crosslinks due to the initial ZnO present, covalent links resulting from peroxide cross-links and further ionic cross-linking due to the generation of ZnO from the decomposition of ZnO 2 . Leaving aside the problem of scorching, ZnO NPs make good and therefore widely used cross-linkers in carboxylated nitrile rubbers.

The prime factors affecting the involvement of ZnO in the formation of ionic cross-links with the carboxylic groups of the elastic polymers are its particle size, surface area and morphology. They are also found to govern the dimensions of the interphase between the cross-linkers and elastomer chains. 114 With a view to ascertain the correlation between the characteristics of ZnO NPs and their roles in the curing of elastic polymers, Przybyszewska et al. 115 employed a variety of ZnO NPs with different morphological characteristics (spheres, whiskers, and snowflakes) as cross-linkers in a carboxylated nitrile elastomer. It emerged from their investigation that ZnO NPs as cross-linkers imparted improved mechanical properties to vulcanizates than commercially used ZnO micro-particles. The ultimate tensile strength of vulcanizates with ZnO NPs was found to be four times higher than that of ZnO micro-particles containing vulcanizates. As a result, there is a 40% reduction of the quantity of ZnO that is put to such use. Since ZnO is known to have deleterious effects on aquatic life, an approach that reduces its usage is highly commendable from the point of view of eco-friendliness. However, ZnO cross-linked XNBR undergoes shrinkage on prolonged exposure to heat.

Among all the aforesaid morphologies, it was observed that ZnO snowflakes with a surface of approximately 24 m 2 g −1 had the highest activity. However, surface area and particle size exerted little influence on the activity of ZnO cross-linkers. It was also observed that the ZnO NPs exhibited a minimum tendency to agglomerate in the rubber matrix. There gathered smaller agglomerates with ZnO NPs as cross-linkers upon sample deformation as compared to the large agglomerates observed with ZnO microparticles.

The usage of ZnO as a cross-linker in rubber has an adverse impact on the environment, particularly when it is discharged into the surroundings upon degradation of rubber. 116 Zinc is known to cause great harm to aquatic species 117 and efforts to cut down on the content of ZnO in rubber are hence being made. 118 Bringing down the ZnO level in rubber, therefore, may follow any of the following three fundamental procedures:

(i) substituting the commonly used micro-dimensional ZnO of surface area 4–10 m 2 g −1 with nano-structured ZnO with surface area of up to 40 m 2 g;

(ii) carrying out surface modifications of ZnO with carboxylic acids ( viz. , stearic acid, maleic acid and the like);

(iii) using additional activators. 119

In order to get over the eco-toxicity associated with the usage of ZnO in large quantities, Thomas et al. 120 designed a few unique accelerators, namely, N -benzylimine aminothioformamide (BIAT)-capped-stearic acid-coated nano-ZnO (ZOBS), BIAT-capped ZnO (ZOB), and stearic acid-coated nano-zinc phosphate (ZPS), to probe their effects on the curing of natural rubber (NR) and thereby its mechanical properties. ZnO NPs prepared by the sol–gel route were surface-decorated using accelerators such as BIAT and fatty acids such as stearic acid. The capping agents functioned to reduce the size of agglomerates leading to an improvement of vulcanization and physicochemical properties of NR. Capping of ZnO further ensured a decline in the time and energy required for dispersion in the rubber matrix. As a result, there happened a further enhancement of the acceleration of vulcanization and a remarkable upgrade of the mechanical properties of the emerging vulcanizates. The rubber vulcanized with an optimal dose of BIAT-capped-stearic acid-coated zinc oxide (ZOBS) was found to possess superlative curing and mechanical properties in comparison with other countertypes and the reference polymer containing pristine ZnO NPs. The rigidity of vulcanizates containing ZPS was found to increase as a result of an enhanced cross-link density. The vulcanizates exhibited reduced tendency to get scorched as a result of incorporation of capped ZnO NPs and this was attributed to the delayed release of BIAT from the capped ZnO into the rubber matrix for interaction with CBS (conventional accelerator). Sabura et al. 121 adopted a solid-phase pyrolytic procedure to synthesize ZnO NPs of particle size in between 15 and 30 nm and surface area in the range 12–30 m 2 g −1 for use in neoprene rubber as cross-linkers. Two findings emerged from this study. One, the optimal content of ZnO required was found to be low in comparison with commercially used ZnO. Two, the cure characteristic and mechanical properties of the rubber showed a marked improvement when compared with those containing conventional ZnO.

5.2 Opto-electronic industry

The last decade has seen an upsurge in the fabrication of ZnO-based perovskite solar cells (PSCs). Although the conventional choice for an electron transport layer has been TiO 2 , ZnO with higher electron mobility is increasingly replacing it as an efficient and low-cost material for electron transport in PSCs. Additionally, the power conversion efficiency of PSCs at large has exceeded 20% of late giving the necessary impetus to delve deep into the fabrication of ZnO electron transport layers (ETLs) for yet more brilliant perovskite solar devices. Bi et al. 134 fabricated a PSC with ZnO nanorods aligned vertically over the substrate. With the length of nanorods, the J sc (short-circuit current density), FF (fill factor) and PCE of solar cells were found to increase. They however reported a decrease in V oc with nanorod length. They reasoned that nanorod length has a bearing on the electron transport time and lifetime that in turn influence the performance of the solar cell. They achieved a maximum overall cell efficiency of 5%. Son et al. 135 substituted the single-step method used by Bi et al. by a two-step coating procedure. Such a treatment generated a fully filled perovskite film that covered all ZnO nanorods of varying lengths without voids and formed an overlayer on the surface of nanorods. As a further consideration, the two-step coating treatment induced optimization of the cuboid size of MAPbI 3 and reduced the series resistance of the solar cell. 136 As a result, a maximum PCE of 11.13% was obtained. Tang et al. designed ZnO nanowall ETLs. 137 The best performance PSC based on ZnO nanowalls produced a J sc of 18.9 mA cm −2 , V oc of 1.0 V, FF of 72.1%, and PCE of 13.6%. Meanwhile, the control device shows a J sc of 18.6 mA cm −2 , V oc of 0.98 V, FF of 62%, and PCE of 11.3%. The introduction of ZnO nanowalls led to an evident boost in the FF and PCE of the PSCs and this can be ascribed to the greater contact area between ZnO and perovskite offered by the ZnO nanowalls in comparison with the planar ZnO film which improves not only the electron collection but also transportation efficiency at the interface of the ZnO nanowalls and perovskite. Moreover, the decomposition of ZnO by perovskite triggered by the alkaline nature of the ZnO surface leads to the formation of PbI 2 on the perovskite/ZnO interface. The presence of PbI 2 can suppress the surface recombination and improve the FF. 138

5.3 Gas-sensing

The electrons injected into the conduction band lower the resistance of the Al-doped ZnO gas sensors. The response and recovery times observed for all Al-loaded ZnO samples were 6–8 s sand 16–30 s, respectively. The unloaded ZnO sample was marked by longer response and recovery times of 30 s and 70 s, respectively. The sensing films exhibited excellent thermo-mechanical and electrical stability.

Therefore, the ZnO/SnO 2 nanocomposite gas sensor demonstrated a sharper response to ethanol gas than the pristine SnO 2 sensor. Moreover, a possible increase in the effective barrier height of the n–n heterojunction enabled better engagement with adsorbed oxygen causing greater depletion of electrons from the conduction band eventually leading to an enhanced gas sensing response by the system. Additionally, remarkable detection at a lower (ppb) limit was shown by the heterostructured sensor.

5.4 Cosmetic industry

In a study by Reinosa et al. , 149 it was brought to light that a nano/micro-composite comprising nanosized TiO 2 dispersed on ZnO micro-particles showed a higher sun protection factor (SPF) than individual TiO 2 and ZnO particles. The SPF of the synthesized nano-sized TiO 2 was found to be higher than that of its micro-sized counterpart with the former showing maximum absorption at 319 nm while the latter showed maximum absorption at 360 nm. The synthesized micro-sized ZnO had a higher SPF than its nano equivalent. Both exhibited maximum absorption at 368 nm. These data suggested that ZnO has a higher critical wavelength because it covers the entire UV range and has a higher UVA/UVB ratio since the maximum of the SPF curve lies in the UVA region ( Fig. 16a ). Additionally, it was observed that TiO 2 , with a lower UVA/UVB ratio owing to the presence of the SPF maximum in the lower wavelength region, has a lower critical wavelength ( Fig. 16b ). Therefore, to boost the SPF output, a suitable combination of the two oxides was thought out. A dry dispersion procedure was adopted to prepare the composite consisting of 15 wt% TiO 2 NPs and 85 wt% ZnO micro-structured particles. The results obtained from this composite were compared with those obtained by the standard procedure. Raman spectroscopy revealed a superior dispersion of the NPs and their anchoring with higher quantum confinement resulting from dry dispersion by using ZnO micro-structures as host particles. The SPF output was found to be higher for the sunscreen with the filter prepared by the dry dispersion method than the one with the filter synthesized following the standard method ( Fig. 17 ). This observation was chiefly attributed by the authors to the correct dispersion of TiO 2 NPs over the host ZnO micro-sized particles.

5.5 Textile industry

It has been shown in many research investigations that the use of ZnO in the processing of fabrics promotes their anti-bacterial and self-cleaning properties apart from upgrading their UV absorption capacity. 158 Moreover, in textile applications, coatings of ZnO in the nano-dimensions aside from being bio-compatible are found to exhibit air-permeability and UV-blocking ability far greater than their bulk equivalents. 159 Therefore, ZnO nanostructures have become very attractive as UV-protective textile coatings. Different methods have been reported for the production of UV-protective textiles utilizing ZnO nanostructures. For instance, hydrothermally grown ZnO nanoparticles in SiO 2 -coated cotton fabric showed excellent UV-blocking properties. 160 Synthesis of ZnO nanoparticles elsewhere through a homogeneous phase reaction at high temperatures followed by their deposition on cotton and wool fabrics resulted in a significant improvement in UV-absorbing activity. 161 Similarly, ZnO nanorod arrays that were grown onto a fibrous substrate by a low-temperature growth technique provided excellent UV protection. 162

Zinc oxide nanowires were grown on cotton fabric by Ates et al. 163 to impart self-cleaning, superhydrophobicity and ultraviolet (UV) blocking properties. The ZnO nanowires were grown by a microwave-assisted hydrothermal method and subsequently functionalized with stearic acid to obtain a water contact angle of 150°, demonstrating their superhydrophobic nature, which is found to be stable for up to four washings. The UV protection offered by the resulting cotton fabric was also examined, and a significant decrease in transmission of radiation in the UV range was observed. The self-cleaning activity of the ZnO nanowire-coated cotton fabric was also studied, and this showed considerable degradation of methylene blue under UV irradiation. These results suggest that ZnO nanowires could serve as ideal multifunctional coatings for textiles.

Research on the use of zinc oxide in polyester fibres has also been carried out at Poznan University of Technology and the Textile Institute in Lodz. 164 Zinc oxide was obtained by an emulsion method, with particles measuring approximately 350 nm and with a surface area of 8.6 m 2 g −1 . These results indicate the product's favourable dispersive/morphological and adsorption properties. Analysis of the microstructure and properties of unmodified textile products and those modified with zinc oxide showed that the modified product could be classed as providing protection against UV radiation and bacteria.

5.6 Antibacterial activity

Epidemic disease cholera mainly affects populations in developing countries. 169,180 It is a serious diarrheal disease caused by the intestinal infection of Gram-negative bacterium V. cholerae. The effective antibacterial activity of ZnO NPs and their mechanism of toxicity were explored against Vibrio cholerae (two biotypes of cholera bacteria (classical and El Tor)) by Sarwar et al. 176 Strong arguments and detailed justifications of the toxicity mechanism emerged as a result of this rigorous investigation. The bacterial membrane bears an overall negative charge that can be ascribed to the acidic phospholipids and lipopolysaccharides in it while ZnO NPs possess a positive charge in water suspension. An initial NP–membrane interaction via electrostatic attraction may result from this charge difference following which membrane disruption occurs. As the membrane plays an essential role by maintaining the vital function of the cell, such damage induces depolarization of the membrane, increased membrane permeabilization – loss in membrane potential and protein leakage and denaturation upon subsequent contact with ZnO NPs. Besides, ZnO NPs also have the ability of interacting with DNA as well as forming abrasions on it. Significant oxidative stress was also noticed inside the bacteria cells. They thus arrived at a conclusion that binding of ZnO NPs with the bacterial cell surface induces membrane damage followed by internalization of NPs into the cells, leakage of cytoplasmic content, DNA damage and cell death. Disruption of the membrane by ZnO NPs would additionally give easy access of antibiotics into the cell. Their findings further corroborated a synergic effect produced by the actions of ZnO NPs and antibiotics. They also encountered the antibacterial activity of the ZnO NPs in cholera toxin (CT) mouse models. It emerged that ZnO NPs could induce the CT secondary structure collapse gradually and interact with CT by interrupting CT binding with the GM1 ganglioside receptor. 181

In bacteria treated with NPs of ZnO, it was observed that the damage to cell membranes was an inevitable phenomenon. The pathways of the antibacterial activity of ZnO NPs were investigated using Escherichia coli ( E. coli ) as a prototype organism. 182 As was evident from the SEM images of E. coli obtained after treatment with ZnO NPs, a greater number of cell damage sites were noted at higher doses of ZnO NPs. This cell damage has been ascribed to pathways involving both the presence and absence of ROS. In the absence of ROS, the interaction of ZnO NPs with bacterial membranes would lead to damage to the molecular structure of phospholipids culminating in cell membrane damage.

Jiang et al. 183 studied the potential antibacterial mechanisms of ZnO NPs against E. coli . They reported that ZnO NPs with an average size of about 30 nm caused cell death by coming into direct contact with the phospholipid bilayer of the membrane and destroying the membrane integrity. The significant role of ROS production in the antibacterial properties of ZnO NPs surfaced when it emerged that the addition of radical scavengers such as mannitol, vitamin E, and glutathione could block the bactericidal action of ZnO NPs. However, the antibacterial effect triggered by Zn 2+ released from ZnO NP suspensions was not apparent. Reddy synthesized ZnO NPs with sizes of ∼13 nm and investigated their antibacterial ( E. coli and S. aureus ) activities. 168 It was discovered that ZnO NPs effected complete cessation of the growth of E. coli at concentrations of about 3.4 mM but induced growth inhibition of S. aureus at much lower concentrations (≥1 mM). Besides, Ohira and Yamamoto 184 also discovered that the antibacterial ( E. coli and S. aureus ) activity of ZnO NPs with small crystallite sizes was far more pronounced than for those with large crystallite sizes. From ICP-AES measurement, it emerged that the amount of Zn 2+ released from the small ZnO NPs was much higher than from the large ZnO powder sample and E. coli was more sensitive to Zn 2+ than S. aureus . This is a further confirmation that eluted Zn 2+ ions from ZnO NPs also play a key role in antibacterial action.

Iswarya et al. , 185 having extracted crustacean immune molecule β-1,3-glucan binding protein (Phβ-GBP) from the haemolymph of Paratelphusa hydrodromus , successfully designed Phβ-GBP-coated ZnO NPs. The Phβ-GBP-ZnO NPs were spherical shaped having a particle size of 20–50 nm and halted the growth of S. aureus and P. vulgaris . S. aureus was found to be more prone to the bactericidal action of Phβ-GBP-ZnO NPs than P. vulgaris . In addition, Phβ-GBP-ZnO NPs could induce drastic modification in cell membrane permeability and set off outrageous levels of ROS formation both in S. aureus and P. vulgaris . This work was thus pivotal in bringing to the forefront the immensely great antibacterial hallmark of Phβ-GBP-ZnO NPs.

The mechanism of breaking into bacterial cells by membrane disruption and then inducing oxidative stress in bacterial cells, thereby stalling cell growth and eventually causing cell death has been reported in many recent research studies. 186–191 Important bacterial biomolecules can also adsorb on ZnO NPs. Bacterial toxicity, in the recent past, has been heavily reported to have resulted from structural changes in proteins and molecular damage to phospholipids. 192 The antibacterial activity of ZnO NPs thus finds its apt application in the discipline of food preservation. As a formidable sanitizing agent, it can be used for disinfecting and sterilizing food industry equipment and containers against attack and contamination by food-borne pathogenic bacteria. ZnO NPs showed both toxicity on pathogenic bacteria ( e.g. , Escherichia coli and Staphylococcus aureus ) and beneficial effects on microbes, such as Pseudomonas putida , which has bioremediation potential and is a strong root colonizer. 193

Investigations into the antibacterial activities of ZnO micro-sized particles, ZnO NPs, and ZnO NPs capped with oxalic acid against S. aureus were carried out in the presence and absence of light. 194 It was observed that the efficiency of ZnO NPs was just 17% in the dark. However, their antibacterial properties saw a surge up to 80% upon application of light. The antibacterial behaviour was greatest for ZnO NPs while it was minimum for ZnO micro-sized particles, suggesting a higher release of Zn 2+ ions from ZnO NPs than ZnO micro-sized particles. The examination revealed that surface defects of the ZnO NPs boosted ROS production in the presence as well as absence of light. Additionally, it was also found that capping lowers the amount of superoxide radicals generated because capping blocks the oxygen vacancies that are chiefly accountable for the generation of superoxide radicals. In another investigation, the influence of NP size on bacterial growth inhibition by ZnO NPs and the mechanistic routes of their action were demonstrated. 195 ZnO NPs with diameters ranging from 12 nm to 307 nm were first generated. Thereafter, they were administered to Gram-positive and Gram-negative microorganisms ( Fig. 18 ). The results clearly illustrated the greater bactericidal efficacy of smaller ZnO NPs under dark conditions. The use of UV light resulted in an enhanced antibacterial behaviour of ZnO NPs owing to the enhanced formation of ROS from them. The antibacterial properties were rooted in the generation of ROS and the build-up of ZnO nano-sized particles in the cytoplasm and on the external membranes.

In another intriguing investigation, the toxicity induced in antibiotic resistant nosocomial pathogens such as Acinetobacter baumannii ( A. baumannii ) and Klebsiella pneumoniae ( K. pneumoniae ) by photocatalytic ZnO NPs was studied. 196 It was seen that A. baumannii and K. pneumoniae were significantly destroyed by 0.1 mg mL −1 of ZnO nano-structures with 10.8 J cm −2 of blue light. Further, the mechanistic pathway of the antibacterial activity of photocatalytic ZnO NPs against antibiotic defiant A. baumannii was investigated. While cytoplasm leakage and membrane disruption of A. baumannii were evident after treatment with ZnO NPs under blue light exposure, there was no sign of plasmid DNA fragmentation. Therefore, membrane disruption could be associated with the mechanistic route via which the photocatalytic ZnO NPs demonstrated antibacterial activity. The possibility of the role of DNA damage therein was categorically ruled out.

A novel approach comprising a combined application of ultrasonication and light irradiation to ZnO NPs has been developed to boost their antibacterial properties. 197 The sono-photocatalytic activity of ZnO nanofluids against E. coli was tested. The results revealed a 20% rise in the antibacterial efficacy of ZnO nanofluids. Further, ROS generation by ZnO nanofluids played a crucial role in bacterial elimination. The sono-photocatalysis of ZnO nanofluids also enhanced the permeability of bacterial membranes, inducing more efficacious penetration of ZnO NPs into the bacteria.

Although ZnO NPs make a promising antibacterial agent owing to their wide-ranging activities against Gram-positive as well as Gram-negative bacteria, the exact antibacterial pathway of ZnO NPs has not been adequately established. Hence, deep investigations into it hold a lot of important theoretical and practical value. In the future, ZnO NPs can be explored as antibacterial agents, such as ointments, lotions, and mouthwashes. Additionally, they can be overlayed on various substrates to prevent bacteria from adhering, spreading, and breeding in medical devices.

5.7 Drug delivery

Reports bearing evidence of the applications of ZnO NPs in the delivery of chemotherapeutic agents to treat cancers have emerged prolifically in the last few years. For instance, a porous ZnO nanorod based DDS (ZnO-FA-DOX), enclosing folic acid (FA) as a targeting agent and doxorubicin (DOX) as a chemotherapeutic drug, was fabricated by Mitra et al. 204 The ZnO-FA-DOX nano-apparatus was found to exhibit pH-triggered release of DOX and potent cytotoxicity in MDA-MD-231 breast cancer cells. The biocompatible nature of the ZnO-FA material, as observed from the acute toxicity study in a murine model also emerged from the investigation. In another research study by Zeng et al. , 205 a lymphatic-targeted DDS with lipid-coated ZnO-NPs (L-ZnO-NPs) enclosing 6-mercaptopurine (6-MP) as an anticancer agent was designed. The L-ZnO-NP apparatus demonstrated pH-susceptive drug release and remarkable cytotoxicity to cancer cells as a result of the generation of intracellular reactive oxygen species (ROS). Liu et al. 206 also reported the fabrication of DOX-loaded ZnO-NPs. The researchers encountered a pH-susceptive drug release from the DDS and diminished drug efflux with enhanced cytotoxicity in drug defiant breast cancer cells (MCF-7R). Likewise, Li et al. 207 fabricated a novel DDS enclosing hollow silica nanoparticles (HSNPs) embedded with ZnO quantum dots to co-deliver DOX and camptothecin. The nano-apparatus evinced pH-susceptive drug release and cytotoxicity to drug defiant cancer cells. A research study used ZnO NPs as caps to cover the pores of mesoporous silica NPs (MSNs), and when the designed drug delivery apparatus came into contact with acids, there took place a decomposition of ZnO NPs followed by a release of doxorubicin (DOX) molecules from the MSN nanostructures. 208 One major drawback of such an apparatus was that it had difficulty in degradation thereby resulting in an incomplete release of drugs. 209,210 Another scheme employed the technique of loading drugs onto the ZnO NPs directly. 211 Upon contact with acids, the drug molecules are released following the complete decomposition of ZnO NPs. In another investigation, a liposome-incorporated ZnO-NP based DDS (ZNPs-liposome-DNR) enclosing anticancer drug daunorubicin (DNR) was designed by Tripathy et al. 212 The incorporation of ZnO-NPs in the DDS was observed to prevent the premature release of DNR, which could be prompted only in acidic medium, thereby efficiently exerting an anticancer effect on A549 cells. The study of intracellular release in cancer cells with confocal laser scanning microscopy (CLSM) revealed that treatment with ZNPs-liposome-DNR induced a marked DNR release, causing greater cytotoxicity to cancer cells, compared to pure DNR and DNR-conjugated liposomes (liposome-DNR), as evidenced by the green fluorescence intensity. For the treatment of lung cancer, Cai et al. accomplished the construction of ZnO quantum dot-based drug delivery apparatus that was conjugated with a targeting agent (hyaluronic acid) and an anticancer agent (DOX). 213 The nano-apparatus demonstrated CD44 receptor-specific uptake and pH-driven drug release in lysosomal compartments of the cancer cells. Kumar et al. 214 also designed sub-micron sized self-assembled spherical capsules of ZnO nanorods that successfully effected the delivery of anticancer agent DOX to K562 cancer cells. Furthermore, Han et al. 215 also synthesized ZnO NPs conjugated with an aptamer as a functionalization agent and DOX as an anticancer agent and demonstrated the effect of combined chemo- and radiation therapy in MCF-7 breast cancer cells employing the nano-apparatus. Recently, Zhang et al. 216 as a part of their investigation devised a new scheme to restrain the proliferation of human hepatocarcinoma cells (SMMC-7721) via a combined application of ZnO nanorod based DNR in photodynamic therapy (PDT), where ROS generation had the possibility to play a key role in the net anticancer behaviour of the hybrid nano-apparatus ( Fig. 19 ). The researchers further discovered that ZnO NPs were able to transport a larger quantity of DNR via internalization into SMMC-7721 cells, thereby inducing outstanding restraint on the multiplication of these cancerous cells. Besides, UV irradiation on this drug delivery nano-apparatus further reinforced the arrest of cell proliferation through photocatalysis of ZnO nanorods. To look into the signaling pathway of anticancer activity of the DDS in PDT, the researchers monitored the caspase-3 activity, which is a hallmark of apoptosis. The results of immunocytochemistry study confirmed that upon treatment with a DNR–ZnO nanocomposite under UV irradiation, the cells demonstrated far more pronounced activation of caspase-3 molecules in cancer-afflicted cells. It was consequently proposed that ZnO nanorods could raise the drug's targeting efficiency and minimize the associated toxicity. Therefore, the DNR–ZnO hybrid nano-apparatus with UV irradiation was claimed to have the potential of a fruitful scheme for the treatment of cancers ( Fig. 20 and 21 ). In another study, Ye et al. 217 using a copolymerization process also prepared water soluble ZnO–polymer core–shell quantum dots, and designed a drug delivery apparatus based on these quantum dots containing Gd 3+ ions and anticancer drug DOX. The ZnO-Gd-DOX nano-system was found to be biocompatible, pH-responsive and led to a marked release of DOX into the acidic environment of cancer-afflicted cells and tumors. When administered to human pancreatic cancer (BxPC-3) tumor containing nude mice, this polymer-modified drug delivery nano-apparatus was found to display higher therapeutic efficiency compared to the FDA-approved liposomal DOX formulation DOXIL at 2 mg kg −1 DOX concentration. The histopathology study and ICP-AES analysis of the vital organs further confirmed that this ZnO-Gd-DOX nano-apparatus could substantially bring about growth-inhibition of tumors without exerting any toxic effects 36 days post administration. Additionally, the histopathology study of tumor sections also demonstrated severe damage to the tumor cells caused by the administration of the DDS, compared to the control, DOX and DOXIL groups.

5.8 Anti-cancer activity

Several studies have thus suggested the cytotoxic effects of ZnO NPs on cancer cells. The cancer cell viability percentage on the MCF7 cell line, A549 cell line, HL60 cell line and VERO cell line has been studied at various concentrations of ZnO. Results show that the cell viability of the above cell lines exhibits a marked decrease with a rise in ZnO concentration 221,222 with minimal damage to healthy cells.

The mitochondrial electron transport chain is known to be closely linked to intracellular ROS generation, and anticancer agents accessing cancer cells could impair the electron transport chain and release huge amounts of ROS. 223,224 However, an inordinate amount of ROS brings about mitochondrial damage thereby resulting in the loss of protein activity balance that eventually induces cell apoptosis. 225 ZnO NPs introduce certain cytotoxicity in cancer cells chiefly by a mechanism that involves a higher intracellular release of dissolved Zn 2+ ions, followed by enhanced ROS induction and induced cancer cell death by way of the apoptosis signaling pathway. The effects of ZnO NPs on human liver cancer HepG2 cells and their possible pharmacological mechanism were investigated by Sharma et al. 226 They observed that ZnO NP-exposed HepG2 cells exhibited higher cytotoxicity and genotoxicity, which were related to cell apoptosis conciliated by the ROS triggered mitochondrial route. The loss of the mitochondrial membrane potential led to the opening of outer membrane pores following which some related apoptotic proteins including cytochrome c were released into the cytosol thereby activating the caspase in due course. Mechanistic studies had proved that the loss of mitochondrial membrane potential-mediated HepG2 cell apoptosis was mainly due to the decrease in mitochondrial membrane potential and Bcl-2/Bax ratios as well as accompanying the activation of caspase-9. Besides, ZnO NPs could noticeably activate p38 and JNK and induce and attract p53 ser15 phosphorylation but this was not dependent on JNK and p38 pathways ( Fig. 21 ). These results afforded valuable insights into the mechanism of ZnO NP-induced apoptosis in human liver HepG2 cells. Moghaddam et al. 227 took recourse to biogenic synthesis and successfully generated ZnO NPs using a new strain of yeast ( Pichia kudriavzevii GY1) and examined their anticancer activity in breast cancer MCF-7 cells. ZnO NPs have been observed to exhibit powerful cytotoxicity against MCF-7 cells. This cytotoxicity is affected more likely via apoptosis than cell cycle arrest. The apoptosis induced by ZnO NPs was largely by way of both extrinsic and intrinsic apoptotic pathways. A few antiapoptotic genes of Bcl-2, AKT1, and JERK/2 were subjected to downregulation, while upregulation of some proapoptotic genes of p21, p53, JNK, and Bax was prompted. ZnO NPs have been widely employed in cancer therapy and reported to promote a selective cytotoxic effect on cancer cell proliferation. Chandrasekaran and Pandurangan evaluated the cytotoxicity of ZnO nanoparticles against cocultured C2C12 myoblastoma cancer cells and 3T3-L1 adipocytes. The study revealed that ZnO NPs could be more cytotoxic to C2C12 myoblastoma cancer cells than 3T3-L1 cells. Compared to 3T3-L1 cells, it emerged that ZnO NPs stalled C2C12 cell proliferation and brought about a more pronounced apoptosis by way of a ROS-conciliated mitochondrial intrinsic apoptotic route, an upregulation of p53, tempered Bax/Bcl-2 ratio, and caspase-3 routes. 228

In a study, biogenic zinc oxide nanoparticles (ZnO NPs) were developed from aqueous Pandanus odorifer leaf extract (POLE) with spherical morphology and approximately 90 nm size. 229 The anticancer activity of the ZnO NPs was evaluated by MTT assay and neutral red uptake (NRU) assays in MCF-7, HepG2 and A-549 cells at different doses (1, 2, 5, 10, 25, 50, and 100 μg mL −1 ). Moreover, the morphology of the treated cancer cells was examined by phase contrast microscopy. The results suggest that the synthesized ZnO NPs inhibited the growth of the cells when applying a concentration from 50–100 μg mL −1 . Overall, the study demonstrated that POLE derived biogenic ZnO NPs could serve as a significant anticancer agent. Phytomediated synthesis of metal oxide nanoparticles have become a key research area in nanotechnology due to its wide applicability in various biomedical fields. The work by Kanagamani et al. 230 explored the biosynthesis of zinc oxide nanoparticles (ZnO-NPs) using Leucaena leucocephala leaf extract. Biosynthesized ZnO-NPs were found to have a wurtzite hexagonal structure with particles distributed in the range of 50–200 nm as confirmed by TEM studies. The anticancer activity of ZnO-NPs against MCF-7 (breast cancer) and PC-3 (human prostate cancer) cell lines was evaluated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. From the assay, biosynthesized ZnO-NPs were found to have better cytotoxic activity on PC-3 cell lines than MCF-7 cell lines. The in vitro cytotoxicity studies of biosynthesized ZnO-NPs against Dalton lymphoma ascites (DLA) cells revealed better antitumor activity with 92% inhibition at a ZnO-NP concentration of 200 μg mL −1 , and as the concentration increased, the anticancer efficiency also increased. These results suggested that ZnO NPs could selectively induce cancer cell apoptosis making them a bright candidate for cancer therapy.

Photodynamic therapy requires the administration of a photosensitizing agent that is subjected to activation by light of a specific wavelength thereby generating ROS. The application of ZnO NPs as effective photosensitizers can be ascribed to their capability to generate ROS in response to visible light or UV light. Recent studies exhibited that photo-triggered toxicity of ZnO NPs renders them aptly suitable for targeted PDT in a spatiotemporal manner, providing a surer way to selectively terminate cancerous cells. 231–234 An attempt was made to utilize the synergic effects of anticancer drugs with ZnO NPs in PDT to induce cell-death in cancer cells. 231 The cytotoxic effects of daunorubicin (DNR), an anti-cancer drug, on drug defiant leukemia K562/A02 cancer cells were put to the test in combination with ZnO NPs. The combination of DNR and ZnO NPs under UV irradiation could appreciably check the proliferation of drug-defiant cancer cells in a dose-dependent manner. Additionally, ZnO NPs were found to induce an enhanced cellular uptake of DNR.

An anticancer treatment using DNR-conjugated ZnO nanorods in PDT was investigated with human hepatocarcinoma cells (SMMC-7721) ( Fig. 19 ). 216 The fabrication of photo-excited ZnO nanorods with DNR displayed an outstanding boost in the anticancer properties of the ZnO nanorods ( Fig. 20 ). The ZnO nanorods raised the intracellular concentration of DNR and augmented the anticancer efficiency. This is further evidence of the drug carrying capacity of ZnO nanorods into target cancer cells. UV irradiation additionally reinforced the growth inhibition of cancerous cells via photocatalytic activity of ZnO nanorods. In this study, the promoted mortality of cancer cells indicates that ZnO nanorods under UV irradiation could efficiently induce the formation of ROS and further attack the cell membrane (mainly by lipid peroxidation), nucleic acids, and proteins (such as enzyme deactivation). The mechanism of ROS generation of ZnO nanorods under UV irradiation is displayed in Fig. 21 . ZnO is a direct band gap semiconductor with a band gap energy of 3.36 eV at room temperature, high exciton binding energy of 60 meV and high dielectric constant, which under UV irradiation will produce a hole (h + ) in the valence band and an electron (e − ) in the conduction band, namely electron/hole pairs. These electron/hole pairs will induce a series of photochemical reactions in an aqueous suspension of colloidal ZnO nanorods, generating ROS. Generally, at the surface of the excited ZnO nanorods, the valence band holes abstract electrons from water and/or hydroxyl ions, generating hydroxyl radicals (˙OH). Electrons reduce O 2 to produce the superoxide anion O 2 − ˙. ZnO nanorods can be one of the promising nanomaterials for PDT in cancer.

The size of ZnO NPs has been reported to have a strong association with their anticancer activities. The UV light-activated anti-cancer effects of various ZnO NPs with different sizes have been examined against human hepatocarcinoma cells (SMMC-7721). 232 To achieve synergetic cytotoxicity, a combination of ZnO NPs and an anticancer agent, DNR, was subjected to investigation. A schematic illustration of the anticancer effect of DNR-conjugated ZnO NPs under UV irradiation is shown in Fig. 22 . The outcome showed higher cytotoxicity of smaller NPs. UV irradiation greatly boosted the cytotoxic effect on SMMC-7721 cells treated with ZnO NPs via generation of ROS and a consequent cell apoptosis. Additionally, when the ZnO NPs were conjugated with DNR, their cytotoxicity against the cancer cells further increased by leaps and bounds.

To secure concomitant intracellular drug delivery and PDT for cancer treatment, poly(ethylene glycol) (PEG)-capped ZnO NPs enclosing DOX were fabricated. 233 It was found that DOX-loaded PEG-ZnO NPs on exposure to UV irradiation achieved significantly enhanced cell cytotoxicity through light-driven ROS production from the NPs. The synergistic anticancer activity of a combined treatment with PEG-ZnO NPs and DOX under UV irradiation came to the fore as a result of this investigation.

Likewise, poly(vinylpyrrolidone) (PVP)-capped ZnO nanorods (PVP-ZnO nanorods) were designed as a drug carrying nano-apparatus for the delivery of daunorubicin (DNR), as well as a photosensitizer for PDT. 234 The DNR-loaded PVP-ZnO nanorods (DNR-PVP-ZnO) encouraged an exceptional upswing in the anticancer activity of DNR due to elevated cellular uptake of the DNR delivered by the nanorods. The DNR-PVP-ZnO nanorods also demonstrated efficient PDT under UV light irradiation. It has been demonstrated that NPs can furnish solutions to confront the acute demerits of conventional photosensitizers. 235 By a dramatic enhancement of the solubility of photosensitizers, NPs can facilitate their increased cellular internalization. They also upgrade the target-specificity of photosensitizers by way of passive targeting to tumor tissues through the enhanced permeability and retention (EPR) effect. Further, cell-specificity of photosensitizers can be remarkably increased by surface modification of the NPs to bind active targeting components. Complexation of ZnO NPs with other photosensitizers has been widely researched to increase the efficacy of ZnO NPs in PDT by synergistically enhancing the ROS generation. 234,235 Meso -tetra( o -aminophenyl)porphyrin (MTAP)-conjugated ZnO nanocomposites were fabricated and examined for synergistic PDT against ovarian cancer cells. 236 The MTAP-ZnO NPs induced generation of ROS upon UV irradiation, the controlling parameters being concentration and light intensity. It emerged that 30 μM MTAP-ZnO NPs wielded high light-induced toxic effects in cancer-afflicted ovarian cells under UV illumination, while they remained inactive in the dark. The cytotoxic activity of MTAP-ZnO NPs under UV illumination was markedly boosted weighed against that of porphyrin alone. 235 This study elucidated the targeted and synergistic PDT by nanoparticles of ZnO loaded with photosensitizing substances. ZnO NPs were combined with protoporphyrin IX (PpIX) as a drug delivery nano-apparatus for photosensitizers. 237 Simple ZnO NPs and PEG-capped ZnO NPs were synthesized and examined for their cancer-eliminating effect against human muscle carcinoma cells. In the absence of laser light, ZnO NPs at 1 mM concentration were found to exert very low cytotoxicity (98% viability). In the presence of 630 nm laser light, PEG-capped ZnO NPs loaded with PpIX exhibited outstanding cytotoxicity owing to the increased ROS generation. Additionally, a high build-up of PpIX in the tumor area was observed when it was delivered by ZnO NPs, exhibiting the potency of ZnO NPs as a tumor-selective drug delivery system for photosensitizers.

5.9 Anti-diabetic activity

A natural extract of red sandalwood (RSW) as an effective anti-diabetic agent in conjugation with ZnO NPs has been tested by Kitture et al. 246 The anti-diabetic activity was evaluated with the help of α-amylase and α-glucosidase inhibition assay with murine pancreatic and small intestinal extracts. Results revealed that the ZnO–RSW conjugate effected a moderately higher percentage of inhibition (20%) against porcine pancreatic α-amylase and proved more effective against the crude murine pancreatic glucosidase than either of the two components alone (RSW and ZnO NPs). The conjugated ZnO–RSW induced 61.93% inhibition in glucosidase while the bare ZnO NPs and RSW exhibited 21.48 and 5.90% inhibition, respectively.

In an investigation conducted to compare the anti-diabetic activity and oxidative stress of ZnO NPs and ZnSO 4 in diabetic rats it was observed that ZnO NPs with small dimensions at higher doses (3 and 10 mg kg −1 ) had a much greater antidiabetic effect compared to ZnSO 4 (30 mg kg −1 ). The observation was backed up by a marvelous decline in the blood glucose level, a steep rise in the insulin level and a refinement of the serum zinc status in a time- and dose-dependent manner. However, it was finally inferred in the study that ZnO nanoparticles severely elicited oxidative stress particularly at higher doses corroborated by the altered erythrocyte antioxidant enzyme activity, enhancement in malondialdehyde (MDA) production, and remarkable drop in serum total antioxidant capacity. 240 Hyperglycemia can squarely trigger off an inflammatory state via activation of C-reactive protein (CRP) and cytokines, such as interleukins, eventually resulting in the development of cardiovascular diseases. Hussein et al. designed ZnO NPs using hydroxyl ethyl cellulose as a stabilizing agent to alleviate diabetic complications. 247 The study demonstrated that ZnO NPs could significantly decrease malondialdehyde (MDA), fast blood sugar and asymmetric dimethylarginine (ADMA) levels. The inflammatory markers, interleukin-1 (IL-1α) and CRP, were also notably lowered after ZnO NP treatment, concomitant with a rise in nitric oxide (NO) and serum antioxidant enzyme (PON-1) levels in diabetic rats.

An investigation was conducted in 2014 into the anti-diabetic potential of ZnO NPs in streptozotocin-induced diabetic albino (Sprague-Dawley) rats. 243 The researchers inferred that the administration of ZnO NPs in diabetic rats brought about a marked lowering of the blood glucose level, boosted the serum insulin level, and elicited the expression of insulin receptor and GLUT-2 proteins, suggesting the inherent capacity of ZnO NPs for diabetic remedy. The anti-diabetic activity of ZnO NPs in streptozotocin-induced diabetic (types 1 and 2) Wistar rats was also demonstrated by Umrani et al. in their research work. 248 The research revealed that ZnO NPs raised the levels of parameters like glucose, insulin, and lipid in rats attesting to the efficient anti-diabetic activity of ZnO NPs. The same research group recently undertook an enquiry into the mechanistic pathway behind the anti-diabetic properties of ZnO NPs in vitro . 249 They demonstrated that ZnO NPs led to protein kinase B (PKB) activation, enhanced glucose transporter 4 (GLUT-4) translocation and uptake of glucose, reduced glucose 6 phosphatase expression, proliferation of pancreatic beta cells, etc. , which were critically responsible for the anti-diabetic behaviour of ZnO NPs. The antidiabetic effectiveness of ZnO nanoparticles prepared using U. diocia leaf extract for treating alloxan-caused diabetic rats was evaluated. 250 From the characterization of the samples, the envelopment of extract over the ZnO-extract sample resulted in individual particles with enhanced properties compared to bulk ZnO. The occurrence of the nettle phytochemicals linked to the ZnO-extract sample was verified by various techniques, especially using TGA, FT-IR, and GC-MS analyses. Among all the employed treatments, the ZnO-extract performed the best for controlling the common complications accompanying diabetes. This biologically produced sample significantly lowered the levels of Fasting Blood Sugar (FBS), Total Triglycerides (TG), and Total Cholesterol (TC) and enhanced the high-density lipoprotein cholesterol (HDLC) and insulin levels in the diabetic rats when compared to the rest of the remedies. The results confirmed the synergistic relationship between ZnO and U. diocia leaf extract where ZnO-extract performed the best compared with the only extract and ZnO. From the results, the as-prepared ZnO-extract sample can be introduced as a non-toxic, applicable, and active phyto-nanotherapeutic agent for controlling diabetes complications.

ZnO nanoparticles were synthesized using a microwave-assisted method in the presence of Vaccinium arctostaphylos L. fruit extract. 251 A decrease in crystallite size was observed for the biologically synthesized ZnO compared to the chemically synthesized sample. Furthermore, the existence of organic moieties over the biologically synthesized ZnO NPs was approved using characterizing methods. Then, the alloxan-induced diabetic rats were divided into an untreated diabetic control group and a normal healthy control group, and the groups received insulin, chemically synthesized ZnO, plant extract, and biologically synthesized ZnO. After treatment, fasting blood glucose (FBS), high-density lipoprotein (HDL), total triglyceride (TG), total cholesterol (TC) and insulin were measured. Analysis showed a significant decrease in FBS and increase in HDL levels in all groups under treatment. However, the results for cholesterol reduction were only significant for the group treated with biologically synthesized ZnO. Despite the changes in the triglyceride and insulin levels, the results were not significant. For all the studied parameters, bio-mediated ZnO NPs were found to be the most effective in treating the alloxan-diabetic rats compared to the other studied treatment agents. All reports of ZnO NPs for diabetes treatment indicated that ZnO NPs could be employed as a promising agent in treating diabetes as well as attenuating its complications.

5.10 Anti-inflammatory activity

5.11 immunotherapy.

5.12 Wound healing

The ensuing results revealed that, two weeks after administration, the synthesized nanocomposite induced a 90% reduction of wound area, while mere 70% wound repair was noted in the control experiment thereby bearing evidence of its commanding wound-fixing capacity. Augustine et al. 270 also fabricated ZnO NP decorated polycaprolactone (PCL) scaffolds and demonstrated that their implantation was able to boost faster wound-fixing by elevating the proliferation and migration of fibroblasts in an in vivo model (wound-healing model of American satin guinea pigs), without showing any marked signs of inflammation. Similarly, Bellare et al. 271 designed biocompatible ZnO NP based scaffolds of gelatin and poly(methyl vinyl ether)/maleic anhydride (PMVE/MA) with remarkable antibacterial effects. Their report threw light on the ability of the scaffolds for endothelial progenitor cell (EPC) adhesion and proliferation. Further, the topical application of the scaffolds on wounds of Swiss/alb mice displayed the potential to expedite the process of wound-fixing. Modern wound care materials suffer from several serious shortcomings that include inadequate porosity, inferior mechanical strength, lessened flexibility, lack of antibacterial properties, etc. Given this backdrop, a CS hydrogel/nanoparticulate ZnO-based bandage which exerted antibacterial effects against both Gram-negative ( E. coli ) and Gram-positive ( S. aureus ) bacteria was fabricated by Kumar et al. 272 The nanocomposite bandage characterized by biodegradability, microporosity and biocompatibility produced elevated wound healing in Sprague-Dawley rats and boosted re-epithelialization and collagen deposition at a remarkable pace. Taking into account the crucial factors of biocompatibility, antibacterial effects, and wound-fixing capacity, the researchers held that the hybrid nanomaterial-based bandage could be valuable for the healing of chronic wounds, burn wounds, diabetic foot ulcers, etc. Likewise, a porous bandage consisting of ZnO NPs conjugated with alginate hydrogel and exhibiting blood clotting capacity and bactericidal effects against E. coli , S. aureus , Candida albicans , and methicillin resistant S. aureus was fabricated by Mohandas et al. 261 The bandage made from the nanocomposite was observed to exhibit biocompatibility at a lower concentration of ZnO-NPs. Further, an ex vivo re-epithelialization investigation with porcine ear skin demonstrated that faster wound-fixing was effected by the hybrid nanomaterial-based bandage than only alginate control bandage. This was ascribed to the release of zinc ions that would enhance the proliferation and migration of keratinocyte cells to the wound area. Nair et al. 273 also developed a bandage consisting of a biocompatible nanocomposite of ZnO NPs conjugated with β-chitin hydrogel. The bandage showed efficient antibacterial activity (against S. aureus and E. coli ) and had the ability of blood clotting and activation of platelets. It was elucidated that the application of the bandage on wounds of Sprague Dawley rats led to faster healing, with enhanced collagen deposition and a reduced number of bacterial colonies than in the control experiment, indicating the remarkable wound repairing capacity of the hybrid nanomaterial-based bandage. A novel, biocompatible ZnO QDs@GO-CS hydrogel was constructed by Liang et al. 274 through the simple assembly of ZnO quantum dots (QDs) with GO sheets and via a simple electrostatic interaction with the loaded CS hydrogel. The antibacterial efficacy could reach 98.90% and 99.50% against S. aureus and E. coli bacteria, respectively, with a low-cost, rapid, and effective treatment. ZnO QDs in antibacterial nanoplatforms could immediately produce ROS and Zn 2+ under acidic intracellular conditions. In parallel, when exposed to 808 nm laser irradiation, hyperthermia from GO sheets could simultaneously kill bacteria. Thus, the excellent performance of the material stems from the combined effects of hyperthermia produced under the near-infrared irradiation of GO sheets, reactive oxygen species, the release of Zn 2+ from ZnO QDs under an acidic environment, and the antibacterial activity of the hydrogel. This work demonstrated that the synergy of antibacterial nanoplatforms could be used for wound anti-inflammatory activity in vivo indicated by the wound healing results. The hybrid hydrogel caused no evident side effects on major organs in mice during wound healing. Therefore, the biocompatible multimodal therapeutic nanoplatforms were proposed to possess great potential for antibacterial activity and wound healing. In a study by Dodero et al. , 275 the possibility of using for biomedical purposes alginate-based membranes embedding ZnO nanoparticles that were prepared via an electrospinning technique was extensively evaluated. The morphological investigation showed that the prepared mats were characterized by thin and homogeneous nanofibers (diameter of 100 ± 30 nm), creating a highly porous structure; moreover, EDX spectroscopy proved ZnO-NPs to be well dispersed within the samples, confirming the efficiency of the electrospinning technique to prepare nanocomposite membranes. Mouse fibroblast and human keratinocyte cell lines were used to assess the biological response of the prepared mats; cytotoxicity tests evidenced the safety of all the samples, which overall showed very promising outcomes in terms of keratinocyte adhesion and proliferation. In particular, the strontium- and barium-cross-linked mats were characterized by similar cell viability results to those obtained with a commercial porcine collagen membrane used as a control; moreover, except for the calcium-cross-linked sample, the prepared mats exhibited a good stability over a period of 10 days under physiological conditions. Antibacterial assays confirmed the proficiency of using ZnO nanoparticles against E. coli without compromising the biocompatibility of the membranes. The mechanical properties of the strontium cross-linked mats were similar to those of human skin ( i.e. , Young's modulus and tensile strength in the range 280–470 MPa and 15–21 MPa for the samples with and without nanoparticles, respectively), as well as the water vapor permeability ( i.e. , 3.8–4.7 × 10 −12 g m −1 Pa −1 s −1 ), which was held to be extremely important in order to ensure gas exchange and exudate removal; furthermore, due to the low moisture content ( i.e. , 11%), the prepared mats could be easily and safely stored for quite a long period without any negative effect on their properties. Consequently, the achieved results demonstrated that the prepared mats could be successfully employed for the preparation of surgical patches and wound healing products by using alginate as an economic and safer alternative to the commonly employed commercial animal collagen-derived membranes.

Ahmed et al. 276 fabricated chitosan/PVA/ZnO nanofiber membranes by using the electrospinning technique. The samples of chitosan/PVA and chitosan/PVA/ZnO tested for antibacterial efficacy and antioxidant potential demonstrated very encouraging results in diabetic wound healing. The nanofiber mats displayed outstanding antibacterial properties against various strains of bacteria. The samples of chitosan/PVA and chitosan/PVA/ZnO nanofiber membranes also manifested higher antioxidant properties which made them promising candidates for applications in diabetic wounds. In experiments involving diabetic rabbits, chitosan/PVA and chitosan/PVA/ZnO nanofiber mats exhibited increased performance of wound contractions in a time interval of 12 days. It was thus concluded in the study that the chitosan/PVA/ZnO nanofibrous membranes could serve as useful dressing materials for diabetic wounds, a major problem for type-2 diabetic patients worldwide.

5.13 Agriculture

5.14 photodegradation.

Ishwarya et al. 73 reported the degradation of methylene blue dye in the presence of ZnO NPs prepared using Ulva lactuca seaweed extract and solar irradiation in their study. With an optimum initial dye concentration of 25 ppm and an optimum catalyst loading of 200 mg, the dye present in 100 mL of water got degraded to 90.4% in 120 min.

Gawade et al. 75 carried out photocatalytic degradation of methyl rrange dye using green fabricated ZnO NPs. 81% of the dye (20 ppm) was degraded after 100 min exposure to UV light. This they carried out after the dye solution was stirred with the catalyst for 30 min in the dark for complete equilibrium of the adsorption–desorption phenomenon when 2% of the dye was found to be adsorbed. The optimum catalyst dose was observed to be 1.5 g dm −3 after the dose had been varied in between 0.1 and 2.0 g dm −3 . The increase in degradation efficiency is ascribed to two favourable factors: (a) an increase in the number of active sites and (b) an increase in the number of photons absorbed by the catalyst. Beyond the optimal quantity of the catalyst, aggregation of the catalyst results in the active sites on the catalyst surface becoming unavailable for light absorption. The turbidity of the suspension leading to the inhibition of photon absorption on the catalytic surface of ZnO NPs because of the scattering effect was cited as an additional cause for the lowered degradation efficiency after the optimal catalyst dose.

Enhanced photocatalytic activity of the Mg doped ZnO/reduced graphene oxide nanocomposite has been recently reported by Nithiyadevi et al. 286 They investigated photodegradation of cationic dyes Methylene Blue (MB) and Malachite Green (MG) under visible light irradiation. They achieved a 94.41% degradation of MB and a 99.56% degradation of MG after exposure to visible light for 75 min in each case. Both the photocatalytic degradations showed a marked increase in efficiency in comparison with that effected by bare ZnO NPs. They obeyed pseudo-first order kinetics and the rate constant assumed values of 0.0391 and 0.0493 min −1 respectively in the case of MB and MG. They cited the following reasons for the enhanced photocatalytic ability of the nanocomposite: (a) the introduction of reduced graphene oxide (RGO) enabled better adsorption of dye molecules through π–π conjugation between the dye and aromatic compounds of RGO, (b) the ability of RGO to facilitate the growth of the ZnO particles on RGO sheets, (c) the availability of a large reactive surface area, (d) the greater interfacial contact between ZnO and RGO, (e) increase in the lifetime of charge carriers most probably attributed to RGO, (f) narrowing of the energy bands of ZnO due to Mg 2+ substitution, (g) presence of oxygen vacancies and (h) the reduction of particle size.

Photodegradation of Methylene Blue (MB) was performed by Debasmita Sardar et al. 287 with an Ag-doped-ZnO nanocatalyst. On increasing the percentage of loaded Ag the rate of photocatalytic decomposition gradually increased and reached the maximum for 20% Ag loading on ZnO. The rate constant was found to be 0.0087 min −1 with a fairly high degradation efficiency of 55.87%. However, a sharp fall in the value of rate constant was observed for 25% Ag loading which remained almost the same on further increasing the Ag content, i.e. for 30 and 35% loading. It was also observed from TEM analysis that too much loading of Ag led to agglomeration and thus covered up the surface of ZnO preventing light absorption. Moreover, there were large numbers of unattached Ag nanoparticles which could be oxidized in the presence of reactive oxygen species. Oxidized silver would not initiate any charge separation in the system. It was thus assumed that silver up to this optimum amount could act as an electron–hole separation centre. Beyond the optimum amount, it could help in charge carrier recombination. In fact, a large number of negatively charged Ag particles (which had already accumulated electrons) on ZnO could capture holes and thus would start acting as a recombination site itself essentially by forming a bridge between an electron and a hole. Thus, the efficiency of charge separation and hence the photocatalytic capability declined to an appreciably large extent.

Very recently, Vaianoa et al. 288 too tried photo-catalytically favourable modification of ZnO by Ag. They too achieved similar results with regard to removal of phenol from water. The loading of Ag responded favourably in the range of 0.14–0.88 wt% but backfired beyond 1.28 wt%. Similar reasons as mentioned above were cited for the trends observed. A photocatalytic test was thus performed by using 0.15 g of the optimized catalyst (1% Ag/ZnO) to treat drinking water containing phenol with an optimized initial concentration of 50 mg L −1 in 100 mL aqueous solution. Near-complete mineralization was accomplished within 180 min of exposure to UV irradiation. Photoreaction was found to fit in the pseudo-first order kinetic model. Another investigation 289 reported a facile microwave assisted synthesis of two-dimensional ZnO nano-triangles with a band gap of around 3.33 eV. The as-synthesized ZnO nano-triangles were applied for the reduction of noxious p -nitroaniline within 50 min. They were further used for the effective elimination of Rose Bengal dye within 150 min.

Likewise, ZnO-nanorods were synthesized 290 by adopting a facile microwave assisted green route of synthesis for the complete reduction of nitro compounds. Lauric acid was used as a complexing and capping agent in the ethanol phase. The nanorods had an average diameter of 5.5–10.0 nm with a hexagonal crystal structure and further demonstrated unusual luminescence properties wherein high intensity UV and yellow emission bands were observed along with negligible blue and green emission bands. Toxic nitro-compounds p -nitrophenol, p -nitroaniline and 2,4,6-trinitrophenol were completely reduced into amino derivatives by NaBH 4 in the presence of these nanorods within 120, 45, and 18 min, respectively.

Chidambaram et al. 291 effectively constructed a ZnO/g-C 3 N 4 heterojunction using a facile, economically viable pyrolysis synthetic route for the photodegradation of methylene blue under visible light illumination. The nanocomposites prepared using 0.1, 0.2 and 0.3 molar ratios of zinc nitrate precursor are labeled 0.1ZnO/GCN, 0.2ZnO/GCN and 0.3ZnO/GCN, respectively. The nanocomposites are found to exhibit a fall in charge recombination corroborated by their photoluminescence spectra that showed a fall in the intensity of the concerned emission peak ( Fig. 25 ). A maximum photodegradation of 86% was achieved with 0.2ZnO/GCN in 60 min following a pseudo-first order kinetic rate constant of 0.032 min −1 while graphitic carbon nitride, 0.1ZnO/GCN and 0.3ZnO/GCN attained 44%, 73% and 76% degradation of methylene blue dye in the same time with lower rate constants. The loading of ZnO over g-C 3 N 4 sheets created a heterojunction ( Fig. 26 ). The excitation of electrons by visible light occurs from the valence band to the conduction band of g-C 3 N 4 . The excited electrons are transferred to the conduction band of ZnO while there occurs a simultaneous movement of holes from the valence band of ZnO to the valence band of g-C 3 N 4 via the smooth interface of the heterostructure. This enabled the generation of the superoxide anion radical and hydroxyl radicals that effected improved mineralization of the dye. An excess of Zn was deemed to cause recombination of photo-induced charges that led to decreased photocatalytic efficiency. In a recent investigation by the authors of the current work, 292 a destructive photocatalyst made up of ZnO nanorods/Fe 3 O 4 nanoparticles anchored onto g-C 3 N 4 sheets was synthesized using hydrothermal synthesis and ultrasonication techniques. HRTEM micrographs shed light on the coupling of Fe 3 O 4 nanoparticles with ZnO nanorods and the successful formation of the intended ternary heterojunction. The g-C 3 N 4 sheets fostered close contact between ZnO nanorods and Fe 3 O 4 nanoparticles thereby inducing a mellowed agglomeration of nanostructured ZnO/Fe 3 O 4 particles. The Tauc plot derived from UV-visible absorbance data showed that the ZnO/Fe 3 O 4 /g-C 3 N 4 nano-hybrid had a band gap of 2.48 eV. PL studies further confirmed the successful development of a staggered type II heterojunction with wide separation between light-induced charge carriers ( Fig. 27 ). The hybrid catalyst showed remarkable photocatalytic activity under visible light, as evident from the efficient degradation of pantoprazole, a pharmaceutical drug widely known as a recalcitrant organic water pollutant. This could be attributed to the synergistic interactions between ZnO, Fe 3 O 4 and g-C 3 N 4 . A degradation efficiency of 97.09% was achieved within 90 min with a remarkable pseudo-first order rate constant of 0.0433 min −1 . The incorporation of Fe 3 O 4 expectedly facilitated the ready recovery of the catalyst and the degradation efficiency displayed fair consistency up to 4 cycles. The work thus offered a cost-efficient strategy for tackling organic water pollutants.

In another study, 293 a facile generation of a quaternary nano-structured hybrid photocatalyst, g-C 3 N 4 /NiO/ZnO/Fe 3 O 4 , was proposed for photodegradation of an ecotoxic pharmaceutical drug, esomeprazole, in aqueous solution. The photocatalytic annihilation of esomeprazole as a prototypical organic contaminant was executed under LED irradiation. By itself the designed ternary heterojunction accomplished a maximum 95.05% photodegradation of esomeprazole and a TOC removal of 81.66% and COD reduction up to 70.68% under optimum conditions of catalyst dose, esomeprazole concentration and pH within 70 min at a superior pseudo-first order kinetic rate constant of 0.06616 min −1 . This actually implied an improvement of degradation over NiO/ZnO, g-C 3 N 4 /NiO and g-C 3 N 4 /ZnO up to ∼74, ∼57, and ∼42%, respectively. The specific reaction rate also went up remarkably by almost ∼3.8, ∼3.18, and ∼2.85 times in comparison with the values obtained for NiO/ZnO, g-C 3 N 4 /NiO and g-C 3 N 4 /ZnO, respectively. The remarkable photocatalytic potential of the heterostructured photocatalyst in practical applications was evident from its reconcilable performances under varying initial concentrations of esomeprazole and initial pH of the solution. The effect of the addition of H 2 O 2 was also put under scrutiny and it was found that the photocatalytic degradation, TOC removal and COD reduction increased to 98.43, 84.72, and 73.86%, respectively, upon addition of an optimum quantity of H 2 O 2 over the same time span. The impacts made by inorganic and organic species on photodegradation and the associated reaction kinetics were investigated and the results were reported. The inhibiting influence of water matrices on esomeprazole degradation was also evaluated for better assessment of the performance of the designed photocatalyst in a real aqueous environment.

CdS/ZnO photocatalysts were prepared by two steps via hydrothermal and photochemical methods for the photodegradation of rhodamine B (RhB) dye. 294 The UV/Vis absorption spectra revealed that the absorption performance of the heterostructure is extended toward the visible light region. The photocatalytic activities of both ZnO nanorod and CdS/ZnO heterostructures were investigated for the photodegradation of RhB dye. It was found that the CdS/ZnO heterostructure prepared with 30 min light illumination shows the best photocatalytic efficiency compared to the one at 15 min and pure ZnO nanorods. The better and enhanced photocatalytic efficiency of the CdS/ZnO heterostructure was ascribed to the high charge separation efficiency. The maximum photocatalytic efficiency of 85% was achieved within 8 h with the CdS/ZnO-30 min photocatalyst.

The photocatalytic degradation of rhodamine B (RhB) over chlorophyll-Cu co-modified ZnO catalysts (Chl-Cu/ZnO) was studied under visible-light irradiation by Worathitanon et al. 295 It was found that chlorophyll as an electron donor and copper in Cu 2+ form help inhibit the recombination of electron–hole pairs and improve the photoactivity of the catalyst. The synergistic effect between chlorophyll and Cu was found to improve the visible-light response of ZnO nanoparticles, resulting in excellent performance in photodegradation of RhB. The appropriate ratio of chlorophyll and Cu loadings over ZnO was 0.5Chl-0.10Cu/ZnO. At this ratio, under visible-light irradiation for 2 h, the degradation efficiency was approximately 99% (60 mg L −1 of RhB solution), of which 18% of RhB adsorption occurred under dark conditions. Moreover, outstanding reusability of Chl-Cu/ZnO, for up to six cycles, was found, with more than 80% degradation efficiency.

In yet another investigation, 296 ZnO nanowires (NWs) were successfully synthesized onto commercially available civil engineering materials using a hydrothermal synthesis method. This easy and low-cost method allowed obtaining an almost homogeneous repartition of nanostructures on the entirety of the surface of the substrates. The measured gap values were similar to those of the ZnO NWs grown on typical substrates, i.e. , ∼3.18 eV and 3.20 eV for concrete and tiling, respectively. The excellent photocatalytic efficiency of our samples was demonstrated on three commonly used dyes, namely, Methyl Orange (MO), Methylene Blue (MB) and Acid Red 14 (AR 14). All of the dyes were fully degraded in less than 2 h for MB and AR 14, and less than 3 h for the more difficult to degrade MO. Investigating the durability of the samples so prepared, very promising results were found, as they showed no loss of efficiency after four experiment cycles. The ability of implementing ZnO NWs on civil engineering materials, their good photocatalytic properties, and the possibility to re-use samples with minimal efficiency losses, even after several months, were found very promising for the use of the nanostructures as road surfaces for air or water depollution.

6. Toxic impacts and mechanisms of ZnO NPs

The toxicity mechanism of ZnO-NPs in zebrafish was investigated by Yu et al. 315 The toxicity caused by ZnO is primarily because of the release of Zn 2+ ions and through mechanical damage in zebrafish. ZnO-NPs induced elevation of intracellular Zn 2+ concentration, leading to over-generation of intracellular reactive oxygen species, leakage of plasma membrane, dysfunction of mitochondria, and ultimately cell death. 316 Therefore, it is demonstrated that cell uptake, intracellular dissolution and release of Zn 2+ are the inherent causes for high toxicity of ZnO-NPs. However, there are some disagreements regarding the role of dissolved Zn 2+ in the toxicity mechanisms of ZnO-NPs. Several researchers suggested that dissolved Zn 2+ from ZnO-NPs played a minor role in the toxicity of ZnO-NPs, 317,318 while other investigations indicated that most of the toxicity of ZnO-NPs is due to the dissolved Zn 2+ . 315,316 This discrepancy may be ascribed to the sensitivities of different organisms to dissolved Zn 2+ , such as single tissue cells, bacteria, zebrafish and so on. In the study of Stella et al. , 319 dissolved Zn 2+ from nZnO was considered to play the vital role in the toxicological mechanisms, which was inferred from the levels of the biomarkers of metallothionein (MT) and heat shock protein 70 (HSP70) in the body of O. melastigma larvae, but this dissolved Zn 2+ was obtained by filtering the ZnO-NP suspensions with a 0.1 μm sterile syringe filter and it might include ZnO-NPs whose diameters were smaller than 100 nm.

The dissolution of Zn 2+ ions from ZnO was also suggested to be the main mechanism for the toxicity of ZnO-NPs as claimed recently. 320,321 Li et al. 322 also reported the same mechanism for the toxicity of ZnO-NPs. They have studied the toxicity of ZnO-NPs with various initial concentrations to E. coli in ultrapure water, NaCl and PBS solutions. For higher concentrations of ZnO-NPs, although a few ZnO particles may attach to the bacterial cells, it was difficult to determine the contribution of nano-ZnO itself considering the high toxicity of co-existing Zn 2+ ions. In addition, bacteria could also release the solutes in response to osmotic down-shock in ultrapure water, resulting in damage to the normal physiological functions and the decrease of tolerance of bacteria to toxicants. 323 Therefore, the toxicity of nano-ZnO at 1 mg L −1 in ultrapure water was much higher than that in 0.85% NaCl solution. To confirm the toxicity mechanism of ZnO-NPs, the ultrastructural characteristics of normal E. coli cells and those treated with ultrapure water, ZnO-NPs, and Zn 2+ ions were investigated with TEM by Li and his research group. The morphologies of E. coli cells treated with ZnO-NPs or Zn 2+ ions were significantly different from those of normal E. coli cells. The cytoplasmic membranes were deformed, wherein some cells swelled and the intracellular substances leaked out under both Zn stress and osmotic stress. Combined with the toxicity results of nano-ZnO, bulk-ZnO, and Zn 2+ ions in ultrapure water, Li and co-workers concluded that the toxicity of nano-ZnO to E. coli was mainly attributed to the released Zn 2+ ions.

7. Challenges and prospects

With higher electron diffusivity than TiO 2 , high electron mobility, exceptionally large exciton binding energy, low cost and considerable stability against photo-corrosion, ZnO has been widely considered a perfect substitute for TiO 2 as the electron transport material in DSSCs and PSCs. However, ineffective surface passivation, interfacial charge recombination and long-term stability have collectively yielded poor electron injection efficiency and thereby low current density and efficiency of the ZnO based photovoltaic device. Probable remedies involve incorporation of organic and inorganic dopants for effective surface passivation and effecting surface modification for marked electronic contact. Poor control of the properties of individual building blocks and low device-to-device reproducibility are further areas that require investigative attention. As a yet further consideration, adequate studies devoted to the impact of facet selectivity, structure and morphology of ZnO nano-structures on the overall efficiency of solar cells and the associated mechanism have to be conducted.

ZnO nanostructured particles have revolutionized the field of photocatalysis. And their efficacy in water splitting and degradation of recalcitrant organic water pollutants has been widely investigated and taken advantage of. However, a few concerning aspects about their photocatalytic activity still need to be dealt with through possible corrective measures. First, the photodegrading ability of a prepared ZnO nano-catalyst needs to be checked by taking the pollutant of interest in lieu of a representative substance which in usual cases is a dye. This is because dye-degradation is relatively plain sailing while removal of pharmaceutical wastes, pesticides, insecticides or other endocrine disruptors offers greater challenges and complicacies. Moreover, the archives of scientific literature are brimming with thorough investigative reports concerning degradation of dyes. Furthermore, waste water contains a mix of different contaminants with varying ranges of pH and ionic strength. Few photodegradation studies have been conducted on organic pollutants in such a simulated sample of water while taking into account the effect of the presence of other contaminants, varying pH and ionic strength on the degradation kinetics. Second, a detailed insight into the mechanistic routes of the degradation of these compounds and their interaction with ZnO based nano-catalysts is elusive as of now and its development remains imperative and will unfold approaches to tackle other emerging contaminants. Third, many improvements in the very architecture of ZnO nanostructures are due specifically in areas such as surface area, particle size, separation and lifespan of charge carriers and so forth. Fourth, since band positions and band gaps are dependent on particle size, it becomes difficult to create heterojunctions able enough to achieve effective charge separation and thereby efficient photocatalytic activity. Systemic studies with a focus on discovering specific synthesis protocols for the achievement of ZnO based nanostructures with desired band positions and band gaps have to be embarked on. Also, there are a few difficulties associated with the operating procedures, such as loss and recovery of nano-structured photocatalysts in the course of post-synthesis treatment and photocatalytic activity. Furthermore, more sweeping research investigations are required to develop and verify the mathematical models for photocatalytic operations/systems for water/wastewater treatment in order to predict the quantum yield, kinetics and optimum conditions of the process.

ZnO nanomaterials may be outstanding candidates as biocompatible and biodegradable nanoplatforms for cancer targeted imaging and therapy. For in vivo imaging and therapy applications, the future of nanomedicine lies in multifunctional nanoplatforms combining both therapeutic components and multimodality imaging. Biocompatibility is also a concern for the applications of nanomaterials in biomedicine. Surface modification of nanomaterials plays a vital role in this context. Biocompatibility of ZnO nanomaterials might be enhanced by slowing down the dissolution rate through Fe doping 324 or surface capping. 325 Therefore, surface coating of ZnO NPs with biocompatible macromolecules, such as poly(lactic) acid, PEG, PEI and chitosan, was attempted to increase their suitability for further clinical usage. Another idea is the synthesis of ZnO nanoplatforms using the biodegradable and biocompatible materials already proven clinically. Some biocompatible polymers, such as liposomes and dendrimers, have been clinically approved for various pharmaceutical applications. Hence, the modification or conjugation of already approved therapeutic formulations or materials with functional ligands which will improve their diagnostic index could be essential. Much effort is needed for long-term in vivo toxicology studies to pave the way for future biomedical applications of these intriguing nanomaterials. Facile conjugation of various biocompatible polymers, imaging labels, and drugs to ZnO nanomaterials can be achieved because of the versatile surface chemistry.

Some other issues of ZnO NPs concerning their biomedical application and their impact on biological systems still need further meticulous inspection. Following are a few such concerns: (a) lack of comparative analysis of the biological advantages of ZnO NPs to other metal nanoparticles, (b) the limitations imposed by the toxicity of ZnO NPs toward biological systems continue to remain a hot potato in recent research, (c) limitations of biocompatible/biodegradable ZnO nanoplatforms for tumor targeted drug/gene delivery, (d) lack of evidence-based research carrying out as its focal point a thorough survey of the therapeutic roles of ZnO NPs in improving anticancer, antibacterial, anti-inflammatory, and anti-diabetic activities, and (e) lack of extensive in vivo investigations into the anticancer, antibacterial, anti-inflammatory, and anti-diabetic activities of ZnO. Fresh studies focused on the abovementioned issues would bring forth further elucidation and comprehension of the potential use of ZnO nanoparticles in biomedical diagnostic and therapeutic fields.

8. Conclusion

Author contributions, conflicts of interest, acknowledgements.

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Plant-mediated green route to the synthesis of zinc oxide nanoparticles: in vitro antibacterial potential

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• Published: 30 July 2024

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• Deniz Kadir Takcı 1 ,
• Melis Sumengen Ozdenefe 2 ,
• Tahsin Huner 3 &
• Hatice Aysun Mercimek Takcı 4  

The plant-mediated, sustainable, facile, eco-friendly, and simple green approaches for the fabrication of metal oxide nanoparticles (NPs) have recently attracted the ever-increasing attention of the scientific community. To date, there has not been any research on green synthesis of ZnO-NPs by Piper guineense (Uziza) seeds widely used as a therapeutic agent is the novelty of the current study. The bioaugmented ZnO-NPs have been manufactured by Uziza seed extract using zinc acetate dihydrate as the precursor and sodium hydroxide with calcination. The hexagonal/spherical crystalline structure at high purely with a mean size of 7.39 nm was confirmed via XRD and SEM analyses of ZnO-NPs. A strong absorption peak at about 350 nm, specific for ZnO-NPs, was observed by a UV-visible spectrometer. The optical bandgap of ZnO-NPs was estimated as about 3.58 eV by the Kubelka-Munk formula. FTIR findings indicated the presence of biofunctional groups responsible for the bioreduction of bulk zinc acetate to ZnO-NPs. The growth rates of E. coli (ATCC 25,922) significantly decreased with ZnO-NPs exhibited compared to the controls. This is making ZnO-NPs promising effective candidates for medical sectors and environmental applications. This current study is hoped to supply a better understanding of the phytosynthesis of ZnO-NPs and promote the advance of green approaches based on plants.

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Introduction

Nanotechnology studies its history dating back to 1959, are now accepted as a modern and revolutionary technology having numerous branches proven in industrial fields [ 1 , 2 ]. The state-of-the-art advances in nanotechnology are many nanoscale device developments showing unexpected popularity in several scientific fields such as biomedicine, environmental and material science, electronics, computing, and optics [ 3 , 4 , 5 , 6 , 7 ]. Nanoparticles have unique physical characteristics that are interrelated and exhibit significant distinction from bulk materials: the high mobility in the free state, the high surface area-to-volume ratio, and the quantum effects [ 8 ]. Nanoparticle dimensions are defined in the range of 1–100 nm and can be classified into their shape, size, and material features. Metallic nanoparticles among these nanostructures possess advanced properties including quantum confinement, optical, plasmon excitation, and large surface energies [ 9 ].

Zinc oxide (ZnO) possessing visible transparency (wide optical bandgap, Eg = 3.37 eV) and high electrical conductivity (large exciton binding energy of 60 meV) is an II-VI semiconducting ceramic material [ 10 , 11 ]. In particular, it has some characteristic features such as inexpensive, biocompatible, non-toxic, high electron mobility, great chemical, and thermal stability, high optical transmittance as well as it is fabricated easily [ 12 , 13 ]. Because of its properties mentioned above and being the most abundant metal oxide after iron, ZnO is one of the most researched nanomaterials [ 14 ]. Due to the uncomplicated control of ZnO properties, ZnO-NPs with various sizes and shapes (flower-like nanostructures, nanowires, nanotubes, nanobelts, nanorings, and nanorods) can be synthesized [ 15 ].

ZnO-NPs might be prepared using many synthesis approaches (chemical, physical, and biological) by manipulating the fabrication mechanisms [ 16 ]. Nowadays, material scientists are focused on costless effective, simple, nontoxic, and eco-friendly methods for the synthesizing of nanoscale materials [ 17 ]. Thus, chemical and physical synthesis strategies have been gradually replaced by biological or “green” methods due to disadvantages such as the release of toxic and harmful chemicals, the requirement of complex and expensive equipment, the necessity of high pressure and temperature, and the consumption of a large amount of energy [ 18 ].

Here, we discuss the plant-based green synthesis of ZnO-NPs using the aqueous extracts of Piper guineense (Uziza) seeds, in Nigeria. The green synthesized ZnO-NPs will be characterized by modern techniques such as scanning electron microscopy (SEM), energy dispersive X-ray analysis (EDAX), ultraviolet (UV-visible) spectroscopy, Fourier transform infrared (FTIR) spectroscopy, and X-ray diffraction (XRD). Besides, the antimicrobial potential of E.coli ATCC 25,922 strain of ZnO-NPs will be exhibited.

Materials and methods

Preparation of seed extract.

The dried seeds of P. guineense (Uziza) (Fig.  1 (a) were purchased from the Ibusa local market in Delta State, Nigeria, in 2023. Seeds (Fig.  1 (b) were firstly washed using distilled water, dried in the sunlight, and then powdered crushing by the electric blender. The powdered seeds (2 g) were soaked in 100 mL distilled for 15 min at 60 °C temperature. After cooling down, the obtained suspension was filtered through a Whatman No.1 filter paper. This seed extract was kept at + 4 °C till used as a reducing and stabilizing agent for NP synthesis [ 19 ].

( a ) P. guineense (Uziza) plant ( b ) Seeds of Uziza

Green synthesis of ZnO-NPs

0.25 g of Zn(CH 3 COO) 2 .2H 2 O was dissolved in 25 mL of seed extract under continuous stirring until a homogeneous mixture for synthesizing ZnO-NPs by green approach. Then, this mixture was heated on a magnetic stirrer at 60 C for 2 h. Following allowed to cool down at 25 °C, the pH of the solution was adjusted to 10 using 2 M NaOH. The solution color of the initially transparent was turned to slightly yellow and finally milky white, indicating the formation of ZnO-NPs. The obtained reaction mixture was centrifuged at 5.000 rpm for 20 min. and the supernatant was discarded. Finally, the remaining pellet was washed three times with distilled water and absolute ethanol and dried in air at room temperature for 3 h. For the yielding of nanomaterial powder products, ZnO-NPs were calcined at 500 °C for 2 h in a muffle furnace to remove any impurities [ 2 ]. Thus, ZnO-NPs were obtained and labeled for further physical characterizations and antibacterial analysis. The green synthesis of ZnO-NPs is schematized in Fig.  2 .

Fabrication scheme of ZnO-NPs using Uziza seeds

Characterization of ZnO-NPs

The physicochemical properties of ZnO-NPs were investigated using different characterization techniques. The elemental composition and surface morphology of ZnO-NPs were inspected using a field emission scanning electron microscope (FESEM, FEI Quanta-FEG-6250) with energy dispersive X-ray analysis (EDX) at 20 kV voltage. The vibrational bands related to the functional group composition of ZnO-NPs were analyzed by a Fourier transform infrared (FTIR) spectrometer (Jasco FT/IR-6700 Spectrophotometer) in the range of 4000–400 cm − 1 . The crystalline nature of ZnO-NPs nanoparticles was exhibited by a Panalytical Empyrean XRD diffractometer Cu Kα radiation (λ = 1.54059 Å) radiation obtained at 45 kV and 40 mA, 10◦ to 90◦ with 0.01◦ step size. The diffuse reflectance spectra of ZnO-NPs were measured using an Ultraviolet-visible spectrophotometer (SHIMADZU UV-3600 PLUS).

Antibacterial assay on Escherichia coli

Bacterial stock cultures of E. coli (ATCC 25,922) were acquired from 80 °C freezer stocks including 30% glycerol. 100 µL of stock solution is transferred into 5 mL of Luria Broth, placed on a shaker (180 rpm), and then incubated for 24 h at 37 °C. The overnight culture of strain was streaked onto Nutrient Agar using a sterile loop and incubated for 12–24 h at 37 °C. Following incubation, a single colony of strain was selected and stocked into the sterile Nutrient Agar for further in vitro anti-bacterial assay.

The antibacterial effect of ZnO-NPs on E. coli was estimated by counting viable bacterial cell concentrations before and after exposure to the NPs. Briefly, the density of the overnight bacterial culture growth in Luria Broth was adjusted to 0.5 on the McFarland scale by saline (0.9% NaCl). 100 µL of this bacterial suspension was inoculated into Luria broth including 25, 50, and 100 µg/mL ZnO-NPs, and incubated at 37 °C for 12 h. Then, an amount of 100 µL of fresh suspension was spread over the surface of Plate Count Agar in triplicate, and plates were incubated at 37 °C for 12–24 h, and colony forming units/milliliter (CFU/mL) were counted. Results were calculated using the equation:

Equation: Cfu(c)-Cfu(s)/Cfu(c)*100.

Results and discussion

P. guineense Schumach & Thonn, also called “West African black pepper, Guinea cubeb, Benin pepper, and Ashanti pepper, has high nutritional qualities, vitamins, and minerals [ 20 ]. It is a culinary spice thriving as native to the tropical rain forest of Africa and also partly cultivated in Southern Nigeria [ 21 ]. Due to its remarkable biological activities such as managing anemia, bronchitis, cancer, carminative, cough, rheumatism, and stomach ache, it is widely used as a traditional source of medicine [ 22 , 23 ]. It is usually named Uziza and Iyre in the South-Eastern Nigerian and Yoruba, respectively [ 24 ]. In addition, numerous phytochemicals, the constituents of crude protein, dry matter, crude fiber, crude lipid, high mineral elements, carbohydrates, and ash were also reported in the dry biomass of Uziza seeds [ 24 , 25 ]. This major substance in Uziza seed biomass is assumed to contribute to the green synthesis of biomedically significant ZnO-NPs.

The fabrication of biogenic ZnO-NPs was performed using aqueous seed extracts of Uziza as reducing, capping, and stabilizing agents. Following the addition of NaOH into the mixture involving Zn(CH 3 COO) 2 .2H 2 O precursor and plant extract, the formation of milky white precipitate was confirmed to be the plant-mediated photosynthesis of ZnO-NPs. The fine white powder obtained subsequently from the washing, drying, and calcination steps was labeled as ZnO-NPs.

The toxic-free substances in Uziza seed extract can be asserted to act as reducing agents that converted the metal precursor to ZnO-NPs. This finding related to phytofabrication was supported by the literature studies revealing the biosynthesis of ZnO-NPs mainly depends on the species of plant used [ 26 , 27 ].

These phytochemical agents are found at different concentrations depending on plant types and have a significant effect on the synthesis, stabilization, and quantity of ZnO-NPs. The bio-reduction mechanism of ZnO-NPs mediated phytochemicals is examined by three main strategies: (1) the activation phase: the bounding of the zinc ions in salt solutions to the reducing metabolites presented in Uziza seed extract, then the reduction of metal ions, and the nucleation of metal atoms. (2) the growth phase referring to Ostwald ripening: Increase in the thermodynamic stability of ZnO-NPs as a result of the coalescing of nearby small NPs spontaneously into larger particles. (3) termination phase: the oxidizing resulting in the linking of metal ions, and the determining of the final shape [ 28 ].

A strong absorption peak of around 350 nm showed the successful synthesis of ZnO NPs via the green approach. This result satisfies the characteristic ZnO absorption peak due to tending to have shorter wavelengths of nanoscale materials [ 29 , 30 ]. The optical bandgap of NPs was estimated by a graph plotted (F(R)hv)2 versus photon energy (hv) in Fig.  3 ’s inset. For a given wavelength the Kubelka-Munk formula adapts the diffuse reflectance data to the function F (R),

where k is the absorption coefficient, R ∞ is the diffuse reflectance, and s is the scattering coefficient. The indirect bandgap of ZnO-NPs was estimated by extrapolation of the linear portion of the (F(R) = 0) curve to the x-axis obtained as 3.58 eV, depending on the sizes of ZnO-NPs. The optical bandgap value agrees with the literature [ 31 , 32 ]. The bandgap of NPs varies depending on various structural factors involving oxygen deficiency, grain size, lattice strain, and surface roughness [ 33 ]. The greater our bandgap value than the bulk ZnO (3.37 eV) may be explained by the small crystallite sizes of photosynthesized NPs.

(F(R)hν)2 versus photon energy (hv) spectrum of ZnO-NPs

The green synthesis of ZnO-NPs mediated Uziza seed extract was displayed by a FE-SEM examination. The size, size distribution, and shape of ZnO-NPs are shown in Fig.  4 (a). The SEM images recorded at a magnification of 10.000x, 50.000x, and 100.000x display that the biosynthesized ZnO-NPs are mostly spherical and well-dispersed without any aggregation. The selected area EDX pattern demonstrates the element compositions of nanoparticles with an average size of 7.39 nm in Fig.  4 (b). The particle shape and size expressed by the SEM were further confirmed using XRD. The shape and size of biogenic ZnO-NPs are closely matched with the values previously reported [ 34 ]. The size and shape of ZnO-NPs play an important role in the antibacterial activity against pathogens. NPs with low size (4.27 nm) and spherical shape tend to penetrate easily into the bacterial cell wall. This is an enormous capability in treating clinical infectious bacterial strains. The purity of synthesized ZnO-NPs and the presence of Zinc in its oxide form were certified by EDX analysis. The strong emission peaks of Zn at ∼ 1 keV, 8.6 keV, and 9.5 keV, and the emission peaks belonging to carbon at ∼ 0.25 keV and oxygen at ∼ 0.5 keV indicated the successful photo-synthesis of ZnO-NPs. The elemental composition of the ZnO-NP revealing 69.38% zinc, 25.12% oxygen, and 5.51% carbon are consistent with the weight peaks that were determined earlier [ 35 , 36 ].

( a ) SEM images of ZnO-NPs at different magnifications and ( b ) elemental composition of ZnO-NPs

The XRD pattern of biosynthesized ZnO-NP mediated Uziza is illustrated by the definite line broadening of the characteristic peaks in Fig.  5 . These Bragg diffraction peaks with 2θ values associated ZnO-NPs identified as 31.9°, 34.6°, 36.4°, and 56.7°, indexed to the (100), (002), (101), and (110) lattice planes, respectively. These peaks matching well with the standard card (JCPDS Card No. 98-002-9272) confirmed the spherical to the hexagonal phase of ZnO-NPs with space group P 63 mc. The absence of any distinctive XRD peaks apart from the sharp ZnO peaks indicates the purity and high crystallinity structure of NPs. These peaks are paralleled to those of previous studies [ 37 , 38 ]. The average crystalline size ( D ) of fabricated ZnO-NPs calculated from the most intense peaks using Debye-Scherrer’s equation:

where λ is the X-ray wavelength (1.5406), k 0.94 is Scherrer’s constant, θ is the FWHM in radians of the peak, and β is the Bragg diffraction angle [ 39 ]. D value depicted from the highest intensity peak corresponding to 101 planes located at position 36.4° is in ranges from 10 nm. The crystalline size of ZnO-NPs detected by Scherrer’s equation is by those of SEM images.

Typical XRD pattern of biogenic ZnO-NPs

As shown in Fig.  6 , the functional groups in the Uziza extract and ZnO-NPs were classified by FT-IR analysis. To demonstrate the organic substances (phenolics and flavonoids) still kept in a structure after the calcination step performed throughout the manufacture of ZnO, the FTIR spectrum of aqueous extract and NPs were compared in Table  1 . Broad absorption peaks at 3435.77 and 3421.62 cm − 1 in a higher energy region are related to the -OH stretching frequency of phenolic and flavonoid components. The absorption bands at 2922.97 and 2924.78 cm − 1 are characteristic of the–C-H-in alkanes N–H or the C = O stretching vibrations, respectively. The following bands at around 1630.66–1627.20 cm − 1 correspond to C = O stretching carboxylic vibration in the amide I and amide II groups. C-H stretching vibrations of the aromatic ring are attributed to the bands (1452.48 and 1422.99 cm − 1 ). The sharp bands at 1012.93 and 1056.53 cm − 1 are due to the–C-N stretching vibrations of aliphatic amines. The other bands at 850.98–844.32 cm − 1 are corresponding to the C-H bending of carboxylic acids and aromatics. The spectral peak at 482.34 cm − 1 corresponded to Zn and O bonding vibrations confirming behaved as a reducing and capping agent phenolic compounds for the synthesized ZnO-NPs. These FT-IR results related to the roles of flavonoids, protein molecules, and the other functional groups in the bioreduction of metal ions were supported by previous findings [ 40 , 41 ]. Our peak regarding the characteristic stretching vibration band of Zn-O at wavelength 469 cm − 1 is in accordance with those of literature findings at 400 to 500 cm − 1 [ 42 ], 450 cm − 1, and 600 cm − 1 [ 35 ], and 486 cm − 1 [ 43 ].

FTIR spectrum of ZnO-NPs and Uziza

The antibacterial efficacy of biogenic ZnO-NPs was scrutinized by counting total viable cells as observed in Fig.  7 . % Inhibition and total viable count (CFU) in cultures exposed to ZnO-NPs at various concentrations are summarized in Table  2 . The strong inhibitory effect of ZnO-NPs on E. coli growth was noted as compared to the control samples without NPs. The highest bactericidal activity was notified as 99.99% in comparison with control (0.0%) regardless of ZnO-NPs concentrations. Our results agree with those of Awwad et al. (2020); Iqbal et al. (2021); Ahmad et al. (2022); Vo et al. (2023) [ 44 , 45 , 46 , 47 ]. The excellent antibacterial efficiency of ZnO-NPs synthesized via the green route depends on having a larger surface area of NPs with smaller sizes and showing one of the possible inhibition mechanisms mentioned in the literature. Antibacterial actions of ZnO-NPs involve (1) the generation of reactive oxygen species (ROS) causing oxidative stress, damage of DNA, and disruption of cell membrane and finally leading to cell lysis; (2) the destroying of the cellular integrity and eventually bacterial cell death by the interaction of ZnO-NPs with bacterial cell membrane, cytoplasm, DNA, RNA, and protein; (3) the direct electrostatic interactions between the bacterial cell wall and ZnO-NPs and the accumulations in the lipid layer resulting in the disruption of plasma membrane and leaking of intracellular components [ 48 , 49 , 50 ].

The viability of E.coli (ATCC 25,922) cells ( a ) without ZnO-NPs and ( b ) with ZnO-NPs at 25, 50, and 100 µg/mL and ( c ) with Uziza extract

Conclusions

Here, we imply a facile, simple, and one-pot eco-friendly green synthesis of biobased ZnO-NPs by P. guineense extract. This current study demonstrated the successful synthesis of hexagonal/spherical ZnO-NPs by reducing, capping, and stabilizing agents indicating the presence of phytochemical compounds in the extract. To the best of our knowledge, this study is the first to research the phytosynthesis of ZnO-NPs by P. guineense from Nigeria. The strong inhibitory ability for biogenic ZnO-NPs on E. coli strain showing high resistance against standard antibiotics is considered to help the developed novel antimicrobial agents to alternative the costly and less efficient drugs that are used in the clinical setup. We hope that our data tenders to the readers to the promising ideas to find out original and up-to-date strategies for metal NPs that can be used in biological systems-related applications.

Data availability

The datasets generated during and/or analysed during the currentstudy are available from the corresponding author on reasonable request.

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Acknowledgements

We thank Harvest Ndubisi Onwordi for providing the Piper guineense (Uziza) plant.

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Deniz Kadir Takcı

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Takcı, D.K., Ozdenefe, M.S., Huner, T. et al. Plant-mediated green route to the synthesis of zinc oxide nanoparticles: in vitro antibacterial potential. J Aust Ceram Soc (2024). https://doi.org/10.1007/s41779-024-01064-0

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Received : 24 April 2024

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DOI : https://doi.org/10.1007/s41779-024-01064-0

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1 Department of Chemistry, School of Science, University of Management and Technology, Lahore, 54770 Pakistan

Sammia Shahid

Sana mansoor, sehrish afzal, mohsin javed, ammar zidan.

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5 Nottingham Ningbo China Beacons of Excellence Research and Innovation Institute, University of Nottingham Ningbo China, Ningbo, 315100 China

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8 Functional Materials Group, Gulf University for Science and Technology, 32093 Mishref, Kuwait

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Associated Data

The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Diabetes mellitus (DM) is a rapidly prevailing disease throughout the world that poses boundless risk factors linked to several health problems. Vildagliptin is the standard dipeptidyl peptidase-4 (DPP-4) inhibitor type of medication that is used for the treatment of diabetes anti-hyperglycemic agent (anti-diabetic drug). The current study aimed to synthesize vildagliptin-loaded ZnO NPs for enhanced efficacy in terms of increased retention time minimizing side effects and increased hypoglycemic effects. Herein, Zinc Oxide (ZnO) nanoparticles (NPs) were constructed by precipitation method then the drug vildagliptin was loaded and drug loading efficiency was estimated by the HPLC method. X-ray diffraction analysis (XRD), UV–vis spectroscopy, FT-IR, scanning electron microscope (SEM), and EDX analysis were performed for the characterization of synthesized vildagliptin-loaded ZnO NPs. The UV–visible spectrum shows a distinct peak at 363 nm which confirms the creation of ZnO NPs and SEM showed mono-dispersed sphere-shaped NPs. EDX analysis shows the presence of desired elements along with the elemental composition. The physio-sorption studies, which used adsorption isotherms to assess adsorption capabilities, found that the Freundlich isotherm model explains the data very well and fits best. The maximum adsorption efficiency of 58.83% was obtained. Further, In vitro, anti-diabetic activity was evaluated by determining the α-amylase and DPP IV inhibition activity of the product formed. The formulation gave maximum inhibition of 82.06% and 94.73% of α-amylase and DPP IV respectively. While at 1000 µg/ml concentration with IC 50 values of 24.11 μg/per ml and 42.94 μg/ml. The inhibition of α-amylase can be ascribed to the interactive effect of ZnO NPs and vildagliptin.

Introduction

Hyperglycemia, a metabolic disease, is the cause of diabetes mellitus (DM) 1 . In adults, 8.8% of people are diagnosed with it yearly 2 . Hyperglycemia results due to inadequate insulin production, poor insulin action, or the combined action of all the two factors. Due to these abnormalities in metabolism, glucose is discharged into the urine 3 . There are three major types of diabetes mellitus i-e Type 1 Diabetes (T 1 DM) 4 , 5 , Type 2 Diabetes (T 2 DM) 6 , 7 , and Gestational Diabetes 8 . The purpose of managing diabetes is to regulate blood glucose levels as close to normal as feasible 9 . Nanomaterials have demonstrated a diverse chemical makeup that includes metal, metal oxide, polymers, silicates, and carbon. These nanomaterials also come in a variety of morphologies, including spheres, sheets, cylinders, or tubes. Size-dependent features include band gap, melting point, mechanical strength, electrical conductivity, optical qualities, magnetic, and catalytic properties 10 . There are three different ways in which these materials can be manufactured including physical 11 , chemical 12 as well as biological 13 . NPs may arise from the reduction of bulk materials to nanoscale scale. Effective absorption is made possible by a decrease in particle size, which increases the surface-volume ratio. Because more active sites on the surface are made available for molecule-to-molecule interaction due to size reduction, the adsorption effectiveness of the NPs is higher than that of their bulk counterparts 14 .

Nowadays metal oxide NPs (MO NPs) are quite important due to their various applications in the field of nano-sensors, catalysis, drug delivery, nanomedicines, wastewater treatment, and electronics 15 , 16 . Metal oxide nanoparticles have demonstrated potential as anti-oxidative, anti-inflammatory, anti-diabetic, and anti-cancer medicines in the field of biomedicine. These nanoparticles' adaptability in the medical arena has also been demonstrated by their use in drug delivery and bio-imaging applications. Because of their special qualities, biocompatibility, and possible therapeutic uses, metal oxide nanoparticles have drawn the attention of scientists looking into cutting-edge methods in nanomedicine and healthcare. The narrow particle size of MO NPs is primarily necessary for successful applications. The generation of the precursor, nucleation, aging, and growth are the four critical processes in the regulated synthesis of MO NPs 17 , 18 . Numerous studies have shown the importance of metals and metal oxides in the metabolism of glucose and their link to insufficient amounts of diabetes. Metal oxide nanoparticles present a multitude of opportunities for diverse applications, ranging from industrial operations to biomedical breakthroughs, underscoring their significance in contemporary scientific investigations and technological innovations. Vanadium 19 , chromium 20 , magnesium 21 , silver 22 , and zinc 23 are all mentioned in the literature as being related to diabetes treatment and blood sugar regulation.

ZnO NPs are well-recognized in countless fields for their astonishing properties and applications 24 . These metal oxide nano-particles showed important physical and chemical properties 25 . Greater antimicrobial, antibacterial 26 , and UV-blocking 27 characteristics have been shown by ZnO NPs. Sol–gel 30 , chemical precipitation 29 , solid-state pyrolysis 31 , solution-free mechano-chemical processes 28 , and biosynthesis 32 are among the techniques used to create ZnO NPs. ZnO NPs play a positive role in diabetes control and their low concentration is enough to enhance insulin secretion 33 . They regulate glucose metabolism, insulin storage, and glucose homeostasis 34 . These NPs also improve the disorders linked to diabetes such as cardiomyopathy and nephropathy 35 .

Vildagliptin is a drug which is used to treat type II diabetes. This is used with exercise and proper diet to obtain better results. It works by causing the pancreas to release more insulin and decrease the hormones that cause the sugar level of blood to rise 36 , 37 . Vildagliptin binds with the DPP-4 enzyme present in the human body and inhibits it. Vildagliptin binds covalently with DPP-4 inhibitor and by doing so they prevent the inactivation of GLP-1 and therefore there is increased plasma concentration of GLP-1. Hence in this way, it increases the levels of GLP-1 bother after intake of meals and fasting. At hypoglycemic levels, the counter-regulatory response of glucagon is increased relative to vildagliptin. The protruding limitation of the drug is having a short half-life which is 2.5 to 3 h. Therefore, to get the desired results high frequency of the drug is needed 38 .

This research aims to synthesize ZnO NPs loaded with Vildagliptin to test their enhanced anti-diabetic activity 39 . The present study is linked to the UN SDG 3 (Good Health and Well-Being). Zinc sulfate heptahydrate (ZnSO 4 .7H 2 O) is used as a precursor material because it may be used with a wide range of precipitation reagents, allowing for a flexible selection of precipitating agents based on the desired properties of the final product. When the novel drug is tailored with the nanomaterials the area of attachment of the drug is increased dramatically. The drug is impregnated to the cellular level due to its nano size. As well as the ZnO NPs also give the maximum protein attachment and synergistic effect against diabetes. By viewing all these aspects this study was aimed to achieve the maximum anti-diabetic activity. The key objective throughout this research work will be the fabrication of ZnO NPs. Adsorption of Vildagliptin on ZnO NPs, characterization of fabricated NPs loaded with vildagliptin by using different techniques, determination of the efficiency of Vildagliptin loaded ZnO NPs against the anti-diabetic activity.

Experimental work

Chemical and reagents.

Since the compounds used in this investigation were analytical grade, no purification was required. ZnSO 4 . 7H 2 O was used as a ZnO precursor and NaHCO 3 used for precipitation was acquired from Merck. Methanol was obtained from Honeywell. Vildagliptin was the API drug purchased from Pharmagen Limited, Pakistan.

Fabrication of ZnO NPs

ZnO nanomaterials were fabricated by the chemical precipitation technique reported earlier 40 . 0.86 g of ZnSO 4 . 7H 2 O was completely dissolved in 30 ml of distilled H 2 O with continuous stirring. 1 M NaHCO 3 solution was inserted dropwise until pH 7 was obtained and precipitates were formed. After one hour of agitation, centrifugation, and a water wash, the product was dried for twelve hours at 120 °C in an oven. After drying, the substance was ground into a powder. Following that, the material was calcined for two hours at 600 °C and then stored for later use. The drying temperature and duration can have a significant impact on the final properties of ZnO nanoparticles. The drying temperature can affect the nanoparticles' crystallinity and phase composition. By pushing solvent molecules to evaporate more quickly, higher drying temperatures may hasten the nucleation and growth of ZnO nanoparticles. The phase purity and crystallinity of the nanoparticles may be affected by this. Phase shifts or crystal defects can also be the result of prolonged drying durations at high temperatures. Figure  1 represents the fabrication method of ZnO NPs. The various parameters that were noticed during the preparations of NPs are listed in Table ​ Table1 1 .

Schematic illustration ZnO NPs.

Distinct construction conditions.

Adsorption of vildagliptin on ZnO NPs

Stock solution 1 mg/ml was prepared in methanol by suspending 100 mg of the drug vildagliptin in 100 ml of methanol. Then sequential dilutions of several contents (0.1, 0.2, 0.3, 0.4, and 0.5 mg/ml) were constructed. For this 25, 20, 15, 10, and 5 ml of stock solutions were taken, and methanol was added to them until the final volume of 40 ml was obtained followed by the addition of 100 mg ZnO NPs. The solutions of different concentrations were continuously stirred at 500 rpm for 5 h by magnetic stirring at room temperature. All solutions were filtered using a vacuum pump with nylon filter paper of 0.45-micron meter. Figure  2 illustrates the adsorption method of the drug on prepared nanomaterials. The previously reported HPLC method 36 was used to determine the percentage of unbound drugs. The drug removal percentage shows the amount of drug loaded and is denoted by P (%). Using the above formulas, the adsorption capacity at equilibrium, represented as q e (mg/g), is measured and calculated.

Adsorption of vildagliptin on ZnO NPs.

ZnO NPs: characterization

For the complete classification of compounds various characterization techniques were used like the Ultraviolet–visible Spectroscopy technique utilizing Shimadzu UV-1800 Japan. To identify the Crystallinity, Crystallite size, and orientation of the NPs X-ray diffraction spectroscopy was carried out with Maker Malvern Panalytical which operates at room temperature. Cu Kα radiation (1.54 Å) source was used to attain the XRD spectra in the range of 10°-80° 41 . Surface morphology and elemental composition were elucidated by SEM and EDX techniques. Both characterizations were assessed by operating Nova Nano SEM-450 “Field-Emission-Scanning-Electron-Microscope (FE-SEM)” with a TLD detector at 1 kV voltage. FTIR spectroscopy was carried out for the structural analysis of prepared NPs. It works by focusing on the various types of bonds and functional groups and is carried out by placing the KBr disk of the sample in front of the IR radiation source 42 . Using an IR-Prestige 21 Shimadzu spectrophotometer, the NPs' IR spectra in the 402–3998 cm –1 range were performed 43 .

Effect of various parameters on the features of ZnO NPs

The various parameters that greatly influenced the properties of ZnO nanoparticles include temperature, drying duration, pH control, and drying conditions. The phase composition and the crystallinity of the fabricated nanomaterials are greatly affected by drying temperature. Greater drying temperatures may accelerate the nucleation and growth of ZnO nanoparticles (ZnO NPs). Prolonged drying durations at high temperatures may result in crystal defects. Faster solvent evaporation and nucleation kinetics at higher temperatures may lead to a smaller particle size. Conversely, slower drying at lower temperatures could lead to larger particle sizes. Through the proper handling of these parameters, the desired results in a range of uses can be obtained, including improved crystallinity, controlled particle size and distribution, optimal shape, and enhanced surface area. The pH was adjusted to 7 during the precipitation step in the synthesis of ZnO nanoparticles using NaHCO 3 solution helps to control the reaction kinetics, prevent unwanted side reactions, control particle size and morphology, and ensure the stability of the nanoparticles, and leads to the desired properties.

Anti-diabetic assay

The percentage inhibition activity of two enzymes named α-amylase and DPP-IV was estimated to check the potential of Vildagliptin-loaded ZnO NPs for the inhibition of diabetic diseases by using an already reported method 44 .

Role of α-amylase

The calcium metalloenzymes known as alpha-amylases are inactive in the absence of calcium. Humans contain a variety of digestive enzymes, the most significant of which is pancreatic alpha-amylase. It catalyzes a reaction that breaks down the alpha-1,4 glycosidic bonds that hold starch, amylopectin, amylose, glycogen, and several maltodextrins together and is thus responsible for the digestion of starch. Alpha-glucosidase, also known as maltase, is another significant enzyme that acts on 1,4-alpha bonds to catalyze the last stage of the digestion of carbohydrates, primarily starch, and produces glucose as a result. Alpha-amylase cleaves large starch molecules to get over the blood–brain barrier, which prevents large molecules like starch from doing so since glucose needs to get to the brain. Excess starch conversion to sugars raises blood sugar levels. Insulin plays a role in this situation by instructing cells to digest the extra sugar molecules and store them as glycogen, which is used as an energy source. When someone is healthy, this cycle never ends. However, there are instances where high blood glucose levels occur as a result of amylase enzyme overactivity, insulin insufficiency, or insulin resistance, which can lead to hyperglycemia 45 .

α-Amylase inhibition activity

Serial dilutions (750, 500, 250 100, and 50 µg/ml) of Vildagliptin-loaded ZnO NPs were prepared. Buffer Solution of pH 7 was prepared and 0.004 g of α- Amylase was dispersed in 100 ml buffer solution to make 2 units of solution 37 . Starch and Dinitro salicylic acid solution was prepared. The sample vials were taken and labeled for different concentrations i.e. Blank, 50,100, 250, 500, and 700 μg/ml. In each vial, 50 μL of solution was taken from respective dilution by using a micro-pipette. 50 μL of alpha-amylase solution was added in each vial. Further total volume of solution in each vial was made to 200 μL by adding about 100 μL of buffer solution (pH 6.9). All these vials were stored in an incubator for 15 min at 37 °C. 50 μL of starch solution was added in each vial containing sample solutions and deposited in an incubator for 15 min at 37 °C. 500 μL of 3,5-Dinitrosalicylic acid (DNS) solution was inserted in all dilutions followed by drying in an oven at 60 °C for 20 min and then allowing it to cool at room temperature (Fig.  3 ). Nothing was added to the control while it was being prepared. The sample solutions were diluted fivefold by adding about 4 ml DMSO. For all dilutions, the UV absorption spectrum was recorded at 540 nm. The following formula was used to calculate the percentage of inhibition of α-amylase.

α-Amylase inhibition activity.

Inhibition of DPP IV

0.0052 g of Gly-Pro-p-Nitroanilide was inserted in 10 ml of cooled distilled H 2 O to create a 1.6 mM solution. Five or six drops of acetic acid were added to maintain the pH at four after 8.2 g of sodium acetate was dispersed in 100 ml of H 2 O. The sample vials were taken, and labeled, and the solutions in each respective vial were for different concentrations i.e., 1000, 750, 500, 250, 100, and 50 μg/ml. In each vial, 25 μL of samples were taken and then, 50 μL of Gly-Pro-p-Nitroanilide (1.6 mM) solution was added. 1 mM buffer solution was added to the above solution to raise the volume to 200 μL. All the solutions were kept in an incubator for about 15 min at a temperature of 37 °C. 50 µL of DPP-IV solution was inserted again and the suspension was then again allowed to incubate at 38 °C for 90 min. Next, a 100 μL solution of sodium acetate was added to halt the process. Figure  4 shows the schematic diagram of DPP-IV Inhibition activity. The control was prepared without adding test samples. UV absorption was recorded for each sample at 405 nm. Using the following formula, the % inhibition of DPP-IV was estimated:

DPP-IV inhibition activity.

IC 50 calculation

The 50% threshold at which inhibition is half-maximized an inhibitory activity's half-maximum concentration is known as its IC50 value. It is represented visually by putting concentration on the x-axis and the % of inhibition along the y-axis. A slope equation can be utilized to calculate the IC 50 value that emerged when the Trend line was chosen as an additive. The concentration that stopped protein denaturation was identified after IC 50 values for the Sample and Standard were obtained.

where Y = Intercept; C = The point at which the line y = mx + c intersects the y-axis; m = The gradient of the line; x = An independent variable.

Results and discussion

Vildagliptin-loaded zno nps: an overview, uv visible spectroscopy analysis.

UV–visible spectroscopy is a technique that is commonly used to investigate the optical properties of zinc oxide (ZnO) nanoparticles (NPs). ZnO nanoparticles typically show a notable absorption peak in the UV region, at 350–380 nm, because they go through electrical transitions from the VB to the CB. UV–visible spectroscopy sheds light on ZnO nanoparticles' optical characteristics and band gap energy. By measuring the samples' absorption spectra in the visible and ultraviolet portions of the electromagnetic spectrum, this technique made it possible to determine the chemical makeup and electronic transitions of the produced nanoparticles 46 , 47 . ZnO NPs were scanned over the wavelength range of 300–400 nm. The maximum absorbance (λ max ) was observed at 367 nm which is also shown in Fig.  5 . This confirms the presence of ZnO NPs because this peak is due to the specific transition of an electron from the VB (O 2p ) to the CB (Zn 3d ) which is also reported in 48 .

UV–visible analysis of ZnO NPs.

FT-IR analysis

The 4000–400 cm -1 range was used to conduct the FT-IR measurements of vildagliptin-loaded ZnO nanoparticles, pure drug, and ZnO nanomaterials (Fig.  6 ). In the spectrum of ZnO NPs, the stretching at 435–450 cm -1 confirms the formation of ZnO NPs 49 . The stretching at 575 cm -1 implies the bond of metal (Zn)-oxygen 50 . The O–H extending because of adsorbed H 2 O molecules at the surface of ZnO NPs shows stretching in the range of 3200–3300 cm -1 51 . In the spectra of Vildagliptin, the stretching at 3294 cm -1 refers to the overlapping of the NH and OH signals 52 . The two (N–O) bonds closest to the metal ion typically showed a symmetrical stretching frequency between 1006 and 1046 cm −1 . The measured signal at 1046 cm −1 therefore indicated that the NO 3 - group was situated within the coordination sphere. The development of a low-rate distinct peak at 510 cm −1 , which was absent from the spectra of the free medicine, indicated the coordination of the O atom of the ketone group and metal band, confirming the complex formation. The stretching vibration of metal–oxygen υ (M–O) was the source of this. The spectra of the free drug showed no υ (M–N) stretching vibrations, which validated the formation of a new peak at 429 cm −1 , suggesting further coordination interaction between the metal and N atom of the secondary amino group 53 . In vildagliptin-loaded ZnO NPs, a smaller number of vildagliptin spectra were observed which explains that drug molecules were present inside the pores of ZnO NPs.

Vildagliptin-loaded ZnO NPs: FT-IR analysis.

XRD analysis

XRD analysis was explored to identify the crystallized aspect of the vildagliptin ZnO NPs. The product’s strong and pointed diffraction peaks are seen in Fig.  7 . This means the product is crystallized to a greater extent. Moreover, the average crystallite size was measured by using the Debye–Scherer formula which is

here D shows average crystallite size; K = Scherer’s constant of value 0.94; λ = wavelength of X-ray source which is 0.15406 nm; β refers to FWHM; θ is the diffraction angle.

XRD analysis of vildagliptin loaded ZnO NPs.

SEM studies

The SEM analysis was enacted to conclude the size, shape, and morphology of the surface. The analysis of Vildagliptin-loaded ZnO NPs was conducted at a high voltage of 10 kV with a TLD detector as shown in Fig.  8 . The analysis showed that ZnO NPs exhibit spherical morphology while ZnO NPs loaded with vildagliptin had a flaky texture. The maximum pores of the NPs were filled by the vildagliptin.

SEM Analysis of Vildagliptin loaded ZnO NPs.

EDX analysis

To ascertain the sample's elemental makeup, EDX analysis was carried out. Vildagliptin-loaded ZnO NPs may usually be subjected to an EDX examination to verify the synthesis process and product purity. This confirms the presence and stoichiometric ratio of zinc, Nitrogen, and oxygen. The examination is simple and gives important information about the elemental makeup of the synthesized nanomaterial as well as any possible contaminants. The EDX spectra of vildagliptin ZnO NPs are shown in Fig.  9 . Table ​ Table2 2 shows the elemental description of the sample which clearly shows that the product was made up of C, O, N, and Zn mainly.

EDX spectra of vildagliptin loaded ZnO materials.

Elemental description of vildagliptin loaded ZnO nanomaterials.

Drug adsorption efficiency

Vildagliptin was subsequently loaded onto ZnO NPs using the batch adsorption technique, after their synthesis by precipitation. In this method, five concentrations of the drug (100, 300, 400, 200, and 500 mg/L) were constructed and the drug loading efficiency was determined by the HPLC method.

The results obtained by this method are summarized in Table ​ Table3. 3 . The maximum adsorption of the drug was seen in 100 mg/L which was 58.83% which dropped to 54.13% as concentration went to 200 mg/L. The minimum adsorption was 44.27% in 500 mg/L concentration which is also explained in Fig.  10 where a graph is plotted between the percentage of drug adsorbed and the concentration of the samples.

Adsorption of vildagliptin by ZnO NPs.

Vildagliptin adsorption using ZnO NPs.

Adsorption isotherm studies

Two alternative isotherm models were compared to which model was optimal for design purposes. Table ​ Table4 4 indicates that the isotherm computations were finalized. The R 2 values in Table ​ Table4 4 and Fig.  11 indicate that the isotherm that most closely matches the data is the Freundlich isotherm. The adsorbent may absorb many layers and have a heterogeneous surface, according to the Freundlich model. Certain important characteristics of the adsorption study may also be investigated based on the information provided by the different isothermal models that were used. These included the vildagliptin adsorption isotherm on the ZnO NP surface, which is shown by the following: Freundlich > Langmuir, with an R 2 value of 0.904. By the Freundlich model, the adsorbent is heterogeneous on the surface and has the potential to adsorb in layers. And correlation coefficient R 2 value must be less than 1 confirming the accuracy of the experimental data as the trendline is straightly following the trend and the adsorption process was in the same right direction there is no deviation in the trend nevertheless proceeding at different serial concentrations. As it is less than 1 also confirms that it was physio-sorption of the drug.

Several isothermal model equations for the investigation of vildagliptin adsorption utilizing ZnO NPs.

Isotherm for Freundlich adsorption.

The preferred and required adsorption type was identified by the Freundlich model, as indicated by the n parameter, which was determined to be (3.84) between 1 and 10. The value of 1/n, at 0.541, was also found to be smaller than the unit, suggesting that heterogeneity occurs on the surface of ZnO NP during the adsorption procedure. The results indicate that, according to the Langmuir model, the experimental q e (200.0 mg/g) is higher than q L (160.4 mg/g). Further support for the positive adsorption process came from the RL, which was found to be 0.196 and was greater than 0 but less than unity. The observed value was 77.2; a value of less than 80 is preferred, and the obtained value was within the acceptable range. Its value of less than 80 suggests that the physisorption mode of adsorption was the most plausible theory.

In the present work, alpha-amylase and DPP-IV inhibition activity of Vildagliptin loaded ZnO NPs at various concentrations is studied and summarized in Table ​ Table5 5 which shows that maximum inhibition 82.06% was obtained at 1000 µg/ml concentration. A graph was plotted shown in Fig.  12 between percentage inhibition and concentration of samples which shows that minimum inhibition 49.74% was at 50 µg/ml. Therefore, it was discovered that the IC50 value for α-amylase activity was 5 µg/ml 54 . The IC 50 of Vildagliptin ZnO nanoparticle concentrations for inhibition of α-amylase was about 24.11 µg/ml.

α-Amylase inhibition capability of vildagliptin loaded ZnO NPs.

There is a reason why ZnO NPs are present and why alpha-amylase is suppressed. As has previously been shown, ZnO NPs themselves have biological roles connected to them 55 . They also exhibit anti-diabetic functions by inhibiting α-amylase. So maximum inhibition was observed by the synergistic effect of NPs and drugs.

Mechanism of action of DPP IV

Polypeptides with praline, alanine, or hydroxyproline residues at the penultimate N-terminal position, like GLP-1, are broken down by DPP IV. The incretin hormones are mostly hydrolyzed at the brush-border membranes of the kidney. The half-life of bioactive peptides, such as GLP-1, is extended by DPP IV inhibitors because they prevent their degradation. Vildagliptin is known to up to 90% suppress DPP IV action, increase endogenous GLP-1 plasma concentrations, prolong the half-life of exogenously administered GLP-1, and lessen postprandial glucose excursions in animal experiments 56 . MicroRNA-103 and microRNA-143 were significantly downregulated in the group of people without diabetes, indicating potential antidiabetic effects of ZnO NPs and the DPP-IV inhibitor vildagliptin, either alone or in combination. Numerous diabetes dysfunction indicators are improved by ZnO NPs, and insulin, including weight reduction, pancreatic SOD efficiency, fructosamine levels, and pancreatic histology. DPP-IV, however, even further improved these indices. Whereas ZnO NPs by themselves had strong antidiabetic effects, vildagliptin combined with ZnO NPs had a synergistic impact on the treatment of diabetes 57 . ZnO NPs and DPP-IV inhibitor (vildagliptin) significantly decreased the expression of microRNA-103 and microRNA-143 in comparison to the diabetic group, either alone or in combination, indicating potential antidiabetic effects. ZnO NPs were shown to improve several diabetes dysfunction markers, including glucose tolerance, pancreatic SOD activity, weight loss, fructosamine levels, insulin levels, and pancreas histology. Additionally, the addition of DPP-IV significantly improved these indices. ZnO NPs by themselves showed significant antidiabetic advantages; however, Vildagliptin added to the mix had a synergistic effect when administered as part of the diabetic treatment regimen.

Further, the ability of vildagliptin-loaded ZnO NPs to inhibit DPP-IV was determined at different concentrations which are 1000, 750, 500, 250, 100, 50 µg/ml. The percentage inhibition activity data is represented in Table ​ Table6 6 .

DPP-IV inhibition activity of vildagliptin loaded ZnO NPs.

Figure  13 represents the graph plotted between percentage inhibition activities against different concentrations of the sample which represents that Vildagliptin-loaded ZnO NPs exhibited better results in the inhibition of DPP-IV. About 94.73% inhibition of DPP-IV was done by Vildagliptin loaded ZnO NPs at 1000 µg/ml concentration with the IC 50 of Vildagliptin loaded ZnO nanoparticle concentrations for DPP-IV inhibition was about 42.94 µg/ml. A minimum inhibition of 52.60% was recorded at a sample content of 50 µg/ml. The inhibitory capability of the enzyme decreased with the lowering of the content of the sample. The rapid release of drugs from nanomaterials can be the reason for the increase in the activity of formulated NPs to inhibit enzyme activity 58 . Quick release allows the drug to be absorbed into the bloodstream more rapidly, resulting in higher concentrations and faster onset of action. It can lead to higher bioavailability, meaning more of the drug is available for the body to use, enhancing its effectiveness. It can improve solubility, making the drug more easily dissolvable and absorbable, leading to increased activity. Rapid release can facilitate targeted delivery to specific sites or tissues, increasing local concentrations and activity. The faster release can promote quicker diffusion into tissues or cells, enhancing drug activity by allowing it to reach its site of action more rapidly. Due to these reasons as discussed above the rapid release of the drug from the formulated Nanoparticles increases the enzyme’s inhibition activity to control hyperglycemia. Table ​ Table7 7 depicts a comparative study of drug adsorption effectiveness.

Comparative study of the drug adsorption efficiency.

In this study, ZnO NPs were constructed by precipitation technique and then an anti-diabetic drug Vildagliptin was loaded on them to enhance the efficacy of the drug. The fabrication of ZnO nanomaterials was established by UV Visible study as λ max of 363 nm was obtained. Vildagliptin was loaded on these ZnO NPs by batch adsorption method and maximum adsorption was observed at 100 mg/ml as determined by HPLC method. The results of SEM explained that drug-loaded nanomaterials exhibit a flaky texture. The Frendulich isotherm was found to be more appropriate for adsorption. In vitro, anti-diabetic analysis was performed, and the percentage of α-amylase inhibition was determined at different contents (50, 500, 100, 250, 750, and 1000 µg/ml). Vildagliptin is an inhibitor of DPP IV but in this work, the drug-loaded ZnO nanomaterials exhibited the inhibition of alpha-amylase too because of the synergistic effect of both ZnO NPs and Vildagliptin. According to the best of our knowledge, the synthesized material has not been previously reported for anti-diabetic activity. The novelty of the work lies in the fabrication of zinc oxide nanomaterials tailored with active drugs to enhance the efficacy of the drugs, particularly in anti-diabetic applications. This represents the increase in receptor sites for the formulation because ZnO NPs themselves have α-amylase inhibition potential and in the end the increase in efficacy of the formulation. The purpose of the study was to investigate how well these drug loaded nanoparticles treat diabetes. The maximum inhibition of 82.06% was seen at 1000 µg/ml. The DPP-IV inhibitory activity of vildagliptin-loaded ZnO NPs at various contents (1000, 500, 750, 100, 250, and 50 µg/ml) was determined which gave a maximum inhibition of 94.73% at 1000 µg/ml. The quick drug release during the incubation period can be the reason for this inhibitory function.

Acknowledgements

The authors extend their appreciation to the Deanship of Research and Graduate Studies at King Khalid University for funding this work under Grant Number RGP2/144/45.

Author contributions

The manuscript was written with the contributions of all authors. All authors have approved the final version of the manuscript.

Data availability

Competing interests.

The authors declare no competing interests.

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Nanoarchitectonics and properties of sol-gel-derived bioactive glasses containing maghemite@ZnO core-shell nanoparticles

• Deliormanlı, Aylin M.
• ALMisned, Ghada
• Tekin, H. O.

This study comprehensively examined the structural, magnetic, hemocompatibility, and bioactivity properties of magnetic bioactive glass particles embedded with zinc oxide-coated superparamagnetic maghemite (γ-Fe 2 O 3 @ZnO) nanoparticles. Bioactive glass particles with varying concentrations of maghemite (2, 5, 10, and 20 wt%) were synthesized using the sol-gel method. The particles ranged in size from 6.83 μm to 14.5 μm, with size decreasing as maghemite content increased. The saturation magnetization values were 1.31 emu/g and 2.74 emu/g for the lowest and highest maghemite concentrations, respectively, indicating superparamagnetic behavior. Hydroxyapatite formation on the glass surfaces diminished with increased maghemite content, but hemocompatibility tests showed no significant hemolytic activity at a concentration of 0.5 mg/ml. The inclusion of γ-Fe 2 O 3 @ZnO nanoparticles significantly enhanced the gamma radiation attenuation properties of the bioactive glasses, particularly at higher maghemite concentrations. In conclusion, γ-Fe 2 O 3 @ZnO-enriched bioactive glasses exhibit promising potential for biomedical applications, offering a balance between magnetic functionality, bioactivity, and radiation shielding. Future research will focus on optimizing nanoparticle concentrations and surface modifications to enhance their multifunctionality.

• Bioactive glass;
• Magnetic nanoarchitects;
• Zinc oxide coating;
• Gamma radiation attenuation;
• Superparamagnetic behavior;